Prescription Drug User Fee Act; Public Meeting, 1743-1753 [07-122]
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Certification Regarding Drug-Free
Workplace Requirements
Alternate I. (Grantees Other Than
Individuals)
The grantee certifies that it will or will
continue to provide a drug-free workplace by:
(a) Publishing a statement notifying
employees that the unlawful manufacture,
distribution, dispensing, possession, or use of
a controlled substance is prohibited in the
grantee’s workplace and specifying the
actions that will be taken against employees
for violation of such prohibition;
(b) Establishing an ongoing drug-free
awareness program to inform employees
about—
(1) The dangers of drug abuse in the
workplace;
(2) The grantee’s policy of maintaining a
drug-free workplace;
(3) Any available drug counseling,
rehabilitation, and employee assistance
programs; and
(4) The penalties that may be imposed
upon employees for drug abuse violations
occurring in the workplace;
(c) Making it a requirement that each
employee to be engaged in the performance
of the grant be given a copy of the statement
required by paragraph (a);
(d) Notifying the employee in the statement
required by paragraph (a) that, as a condition
of employment under the grant, the employee
will—
(1) Abide by the terms of the statement;
and
(2) Notify the employer in writing of his or
her conviction for a violation of a criminal
drug statute occurring in the workplace no
later than five calendar days after such
conviction;
(e) Notifying the agency in writing, within
10 calendar days after receiving notice under
paragraph (d)(2) from an employee or
otherwise receiving actual notice of such
conviction. Employers of convicted
employees must provide notice, including
position title, to every grant officer or other
designee on whose grant activity the
convicted employee was working, unless the
Federal agency has designated a central point
for the receipt of such notices. Notice shall
include the identification number(s) of each
affected grant;
(f) Taking one of the following actions,
within 30 calendar days of receiving notice
under paragraph (d)(2), with respect to any
employee who is so convicted —
(1) Taking appropriate personnel action
against such an employee, up to and
including termination, consistent with the
requirements of the Rehabilitation Act of
1973, as amended; or
(2) Requiring such employee to participate
satisfactorily in a drug abuse assistance or
rehabilitation program approved for such
purposes by a Federal, State, or local health,
law enforcement, or other appropriate
agency;
(g) Making a good faith effort to continue
to maintain a drug-free workplace through
implementation of paragraphs (a), (b), (c), (d),
(e) and (f).
(B) The grantee may insert in the space
provided below the site(s) for the
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performance of work done in connection
with the specific grant:
Place of Performance (Street address, city,
county, state, zip code) .
lllllllllllllllllllll
lllllllllllllllllllll
Check if there are workplaces on file that
are not identified here.
Alternate II. (Grantees Who Are Individuals)
(a) The grantee certifies that, as a condition
of the grant, he or she will not engage in the
unlawful manufacture, distribution,
dispensing, possession, or use of a controlled
substance in conducting any activity with the
grant;
(b) If convicted of a criminal drug offense
resulting from a violation occurring during
the conduct of any grant activity, he or she
will report the conviction, in writing, within
10 calendar days of the conviction, to every
grant officer or other designee, unless the
Federal agency designates a central point for
the receipt of such notices. When notice is
made to such a central point, it shall include
the identification number(s) of each affected
grant.
[FR Doc. E7–374 Filed 1–12–07; 8:45 am]
BILLING CODE 4184–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2007N–0005]
Prescription Drug User Fee Act; Public
Meeting
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice of public meeting.
SUMMARY: The Food and Drug
Administration (FDA, we) is publishing
proposed recommendations for the
reauthorization of the Prescription Drug
User Fee program for the process of
human drug application review for
fiscal years (FY) 2008 to 2012. These
proposed recommendations were
developed after discussions with
regulated industry and consultation
with appropriate scientific and
academic experts, healthcare
professionals, and representatives of
patient and consumer advocacy groups.
Section 505 of the Public Health
Security and Bioterrorism Preparedness
and Response Act of 2002, enacted June
12, 2002, directs FDA to publish these
proposed recommendations in the
Federal Register; hold a meeting at
which the public may present its views
on such recommendations; and provide
for a period of 30 days for the public to
provide written comments on such
recommendations.
DATES: The public meeting will be held
on February 16, 2007, from 9 a.m. to 5
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1743
p.m. Submit written comments by
February 23, 2007. Registration to attend
the meeting must be received by
February 2, 2007.
ADDRESSES: The meeting will be held at
the Grand Hyatt Washington at
Washington Center, 1000 H St. NW.,
Washington, DC 20001. Located at the
Metro Center metro stop. Follow 11th
St. exit to the lobby of the Grand Hyatt.
For additional directions, see the hotel
Web site at: https://
grandwashington.hyatt.com/hyatt/
hotels/.
Submit written comments to the
Division of Dockets Management (HFA–
305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville,
MD 20852. Submit electronic comments
to https://www.fda.gov/dockets/
ecomments.
FOR FURTHER INFORMATION CONTACT:
For information regarding this
document, contact: Ann Sullivan,
Office of Policy and Planning (HFP–
20), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD
20857, 301–827–5887, FAX: 301–
827–5225, e-mail:
Ann.Sullivan@fda.hhs.gov.
For information regarding registration,
contact: Bernadette Kawaley, Office
of Communication, Training and
Manufacturers Assistance (HFM–
49), Food and Drug Administration,
Center for Biologics Evaluation and
Research, 1401 Rockville Pike, suite
200N, Rockville, MD 20852, 301–
827–2000, FAX: 301–827–3079.
SUPPLEMENTARY INFORMATION:
I. Introduction
The Prescription Drug User Fee Act
(PDUFA I), first enacted in 1992 (Public
Law 102–571, October 29, 1992),
authorized FDA to collect user fees from
regulated industry that were to be
dedicated to expediting the review of
human drug applications in accordance
with certain performance goals
identified in letters from the Secretary
of Health and Human Services to the
Chairman of the Energy and Commerce
Committee of the House of
Representatives and the Chairman of the
Labor and Human Resources Committee
of the Senate (138 Cong. Rec. H9099–
H9100 (daily ed. September 22, 1992)).
In 1997, as PDUFA I expired, Congress
passed the Food and Drug
Administration Modernization Act
(FDAMA, Public Law 105–115).
FDAMA included, among other things,
an extension of PDUFA (PDUFA II) for
an additional 5 years. In 2002, Congress
extended PDUFA again for 5 years
(PDUFA III) through the Public Health
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Security and Bioterrorism Preparedness
and Response Act (Public Law 107–
188).
Before PDUFA, FDA’s review process
was more unpredictable, and slower. At
the same time, regulators in other
countries were able to review products
faster. Access to new medicines for U.S.
patients lagged behind. For example, a
1989 study by researchers at Tufts
University, analyzing differences in the
number of new drugs introduced and
time to marketing in the United
Kingdom compared to the United States
for the period 1977 to 1987, found that
the United Kingdom led the United
States in the number of first
introductions of new drugs (114 versus
41) and in the average lead time for
mutually available drugs (60.7 months
lead time in the United Kingdom versus
28.9 months in the United States) and
in the number of exclusively available
new drugs (70 versus 54).1 In addition,
a 1992 review of the international
literature related to drug lag found that
most studies reported the United States,
Sweden and Norway to have a long
delay in the introduction of new drugs,
while the United Kingdom and (West)
Germany were generally found to have
the shortest delay.2 Chronic
understaffing of drug review and related
delays in U.S. patient access to new
drugs led to the 1992 enactment of
PDUFA. PDUFA provided FDA with
added funds that enabled the agency to
hire additional reviewers and support
staff and upgrade its information
technology systems to speed the
application review process for new
drugs and biological products without
compromising FDA’s high standards for
approval.
Since the beginning of the PDUFA
program, there has been a significant
improvement in FDA funding for the
drug review program, including
significant investments in information
technology. PDUFA has enabled FDA to
virtually double the staff dedicated to
the process of reviewing human drug
applications since 1992.
Under PDUFA, the industry provides
additional funds through user fees that
are available to FDA, in addition to
appropriated funds, to spend on the
human drug review process. Our
authority to collect user fees is
1 Kaitin, K.I., N. Mattison, F.K. Northington, L.
Lasagna, The drug lag: an update of new drug
introductions in the United States and in the United
Kingdom, 1977 through 1987,Clinical
Pharmacology and Therapeutics, 1989; 46 (2):121–
38.
2 Andersson, F., The drug lag issue: the debate
seen from an international perspective,
International Journal of Health Services, 1992;
22(1): 53–72.
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‘‘triggered’’ only when a base amount of
appropriated funds, adjusted for
inflation, is spent.
In conjunction with PDUFA, FDA set
review performance goals that became
more stringent each year. These goals
applied to the review of original new
human drug and biological product
applications, resubmissions of original
applications, and supplements to
approved applications. During the first
few years of PDUFA I, we eliminated
backlogs of original applications and
supplements that had formed in earlier
years when the program had fewer
resources. Phased in over the 5 years of
PDUFA I, the goals were to review and
act on 90 percent of priority new drug
applications (NDAs), biologics license
applications (BLAs), and efficacy
supplements (i.e., submissions for
products providing significant
therapeutic gains) within 6 months of
submission of a complete application; to
review and act on 90 percent of
nonpriority original NDAs, BLAs, and
efficacy supplements within 12 months,
and on resubmissions and
manufacturing supplements within 6
months. Over the course of PDUFA I, we
exceeded all of these performance goals.
Under PDUFA II, some review
performance goals continued to shorten.
For example, by 2002, the PDUFA II
goals called on us to review and act on
90 percent of the following:
• Standard new drug and biological
product applications and efficacy
supplements within 10 months,
• Chemistry and manufacturing
control supplements requiring prior
FDA approval within 4 months, and
• Class 1 resubmissions (that respond
to relatively minor deficiencies such as
labeling changes) within 2 months.
In addition, PDUFA II added a new
set of goals intended to improve our
interactions with industry sponsors
during the early years of drug
development, again with the goal of
making promising new drug therapies
available to patients sooner. For
example, these procedural goals called
for us to meet with sponsors and
provide followup meeting minutes
within a certain number of days, and
provide responses to questions on
industry submitted special study
protocols within a certain number of
days. For example, PDUFA II goals
called for us to respond to 90 percent of
industry requests:
• Scheduling Type A meetings within
30-calendar days of FDA receipt of the
meeting request,
• Scheduling Type B meetings within
60-calendar days of FDA receipt of the
meeting request,
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• Scheduling Type C meetings within
75-calendar days of FDA receipt of the
meeting request, and
• Completing written assessments of
the adequacy of special protocols within
45 days of sponsor requests.
However, the agency experienced a
much heavier review workload than was
accounted for by PDUFA II fee funding.
By the end of PDUFA II, the program
was beginning to falter in terms of both
performance and financial stability.
Although we were able to meet the letter
of the performance deadlines in many
cases, FDA reviewers were not able to
allocate time for earlier and more
frequent communication and feedback
to sponsors that might have resulted in
better-quality applications and a higher
rate of first-cycle approvals.
Under the current program,
reauthorized in 2002 (PDUFA III),
additional money from user fees was
authorized to better finance the
expanded scope and growing volume of
demand for FDA review and
consultation, and a mechanism was
placed in PDUFA to annually adjust fee
revenues for increases in workload
associated with the process for the
review of human drugs. For the first
time, PDUFA III also authorized FDA to
spend user fee funds on certain aspects
of postmarket risk management. The
review performance and procedural
goals associated with PDUFA III were
similar to those under PDUFA II for FY
2002 performance levels, but the
PDUFA III program addressed drug
safety issues and established several
new initiatives to improve application
submissions and agency-sponsor
interactions during drug development
and application review. The goals under
PDUFA III included new provisions, for
example, to develop guidance for
industry on good risk assessment, risk
management, and pharmacovigilance
practices; to fund outside expert
consultants to help evaluate and
improve review management processes;
and to centralize accountability and
funding for all PDUFA information
technology initiatives and activities.
Furthermore, in conjunction with
PDUFA’s reauthorization in 2002, FDA
set the goal of creating a guidance for
our review staff and industry on good
review management principles and
practices (GRMPs) as they apply to the
first cycle review of NDAs, BLAs, and
efficacy supplements. We also set a goal
of evaluating whether providing early
review of selected applications and
additional feedback and advice to
sponsors during drug development for
selected products can shorten drug
development and review times. Two
‘‘continuous marketing application’’
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(CMA) pilot programs were initiated.
CMA Pilot 1 provides for the review of
a limited number of presubmitted
portions of NDAs and BLAs. Under
CMA Pilot 2, FDA and applicants can
enter into agreements to engage in
frequent scientific feedback and
interactions during the investigational
new drug phase of product
development.
When it enacted PDUFA III, Congress
enacted special provisions regarding
public accountability in the
development of recommendations for
PDUFA IV. Congress directed FDA,
when developing recommendations to
the Congress for PDFUA IV, to ‘‘consult
with the Committee on Energy and
Commerce of the House of
Representatives, the Committee on
Health, Education, Labor, and Pensions
of the Senate, appropriate scientific and
academic experts, health care
professionals, representatives of patient
and consumer advocacy groups, and the
regulated industry’’ (Section 505.
Accountability and Reports).
In preparing our proposed
recommendations for PDUFA
reauthorization, we have conducted
technical discussions with regulated
industry and have consulted with
stakeholders as required by law. We
began our public consultation on
PDUFA reauthorization with a public
meeting held on November 14, 2005 (
https://www.fda.gov/OHRMS/DOCKETS/
98fr/05–20875.htm).
The meeting included presentations
by FDA and a series of panels
representing different stakeholder
groups, including patient advocates,
consumer groups, regulated industry,
health professionals and academic
researchers. The stakeholders were
asked to respond to the following
questions: (1) What is your assessment
of the overall performance of the
PDUFA program thus far and (2) What
aspects of PDUFA should be retained, or
what should be changed, to further
strengthen and improve the program?
There was general agreement among
the responding stakeholders that
PDUFA should be reauthorized. Most
expressed the view that drug review
should not only include safety and
effectiveness review prior to marketing
approval, but also should encompass
continued safety monitoring after
approval. Many panelists supported
increased PDUFA funds for postmarket
drug safety surveillance, including
developing and monitoring risk
management tools. A number of
panelists also expressed support for
increased resources to fund the review
of direct-to-consumer (DTC) advertising.
Some panelists expressed concern that
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over-emphasizing safety might delay
patient access to new treatments, and
some expressed support for PDUFA
funding of ‘‘Critical Path’’ projects to
help speed new drug development (see
https://www.fda.gov/oc/initiatives/
criticalpath/).
In addition to our initial public
meeting in November 2005, we held
followup meetings to obtain further
input on the PDUFA program and
suggestions regarding what features
should be proposed or amended with
program reauthorization.
On May 22, 2006, we held a meeting
with patient advocacy groups. Overall,
these groups supported reauthorization
of PDUFA as a vehicle for speeding
patient access to safe and effective drug
therapies. They also suggested that user
fees be increased to sufficiently fund
postmarket safety activities and that the
issues raised in the March 2006 GAO
report entitled, ‘‘Drug Safety:
Improvement Needed in FDA’s
Postmarket Decision-making and
Oversight Process’’ (GAO–06–402)
https://www.gao.gov/new.items/
d06402.pdf report on drug safety be
addressed. In addition, it was suggested
that FDA establish postmarket
performance goals, such as milestones
for development of a better postmarket
safety system.
On May 23, 2006, FDA held a meeting
with consumer advocacy groups to get
their input on PDUFA reauthorization.
Some consumer groups indicated a
preference for full funding of human
drug review with appropriated funds
rather than user fees, but they generally
considered fee-funding to be inevitable
and PDUFA reauthorization to be
necessary. Given this, the consumer
advocacy groups who participated in
the meeting emphasized that user fees
should be used to enable the agency to
adequately cover its priorities, but there
should be no ties between user fees and
performance goals. They also expressed
the view that appropriated funding
should be increased and there should be
increased funding to enhance FDA’s
capacity for postmarket safety and DTC
advertising review. Some consumer
advocates further suggested that FDA
charge separate fees for DTC advertising
review.
On June 23, 2006, we held a meeting
with health professional groups to
obtain their views and suggestions for
reauthorization. The health professional
groups supported PDUFA
reauthorization to maintain an efficient
process and the availability of safe and
effective new drugs on the market. They
also thought sufficient funding was
needed to maintain a competent
scientific staff. The health professional
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groups thought PDUFA fees should be
increased to support safety surveillance
and risk management, and the current
statutory time period for using fee funds
for safety-related work should be
eliminated or expanded. They also felt
that fee-funded support for risk
management plans should be expanded
to include older drugs as well as those
recently approved. They indicated that
the issues raised in the March 2006
GAO report on drug safety needed to be
addressed. Finally, they suggested that
PDUFA funds be increased to support
the review of DTC advertising.
Congress also directed FDA to publish
in the Federal Register the proposed
recommendations developed through
this process after negotiations with the
regulated industry, present the proposed
recommendations to the congressional
committees specified in the statute, hold
a public meeting at which the public
can present its views on the proposed
recommendations, and provide for a
period of 30 days for the public to
provide written comment on the
proposed recommendations.
We have now concluded discussions
with industry and other stakeholders
regarding reauthorization of PDUFA.
The purpose of this document is to
publish the recommendations we intend
to propose to Congress and announce
the dates for the upcoming public
meeting and written comment period.
After the public meeting and the close
of the 30-day comment period, we plan
to undertake a careful review of all
public comments on these proposed
recommendations.
II. What We Are Proposing to
Recommend for PDUFA IV
For PDUFA IV, as described in the
following paragraphs, we plan, with a
few exceptions, to carry forward the
performance goals from PDUFA III and
we propose additional goals related to
proposed enhancements to the program.
Our proposed recommendations fall
into three major categories: (1) Proposals
to ensure sound financial footing for the
human drug review program; (2)
proposals to enhance the process for
premarket review of human drug
applications; and (3) proposals to
modernize and transform the
postmarket safety system. In addition,
we are proposing to recommend a
program separate from, but related to,
PDUFA pertaining to fees assessed for
advisory reviews of DTC television
advertisements. The summary table
containing the proposals and related
fees under PDUFA IV can be found in
table 1 of this document. The discussion
and additional fee estimates in this
section (II) and table 1 of this document,
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do not include our proposals and
proposed fee revenue figures for review
of DTC television advertisements. Those
proposals are provided in section III of
this document.
TABLE 1.— PDUFA IV FINANCIAL BASELINE AND ENHANCEMENTS (STARTING IN FY 2008)
Financial Baseline
Dollars
FY 2007 Baseline—Adjusted for Inflation
FTE
$305,455,400
1539
Inflation Adjustment for FY 2008
$17,716,600
Adjustment for Increased Rent and
Rent-Related Costs
$11,721,000
Adjustment for Increased Work per
IND & NDA PDUFA III
$20,000,000
87
$354,893,000
1626
Premarket—Expediting Drug Development
$4,600,000
20
Premarket—Improving IT Infrastructure for Drug Review
$4,000,000
Postmarket—Modernizing and Transforming Safety System
$29,290,000
82
$392,783,000
1728
PDUFA IV Baseline Before Enhancements
Enhancements
PDUFA IV Total1 (in FY 2008)
1Further workload adjustment, to account for work levels in FY 2007, is expected to add about $45,000,000 and 195 FTEs for a final total of
about $437,800,000 and 1923 FTEs for FY 2008.
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A. Proposed Recommendations to
Ensure Sound Financial Footing
Although user fees have provided
substantial resources to FDA since the
beginning of the program, user fees have
not kept up with the increasing costs of
the program associated with inflation in
pay and benefit costs to the agency, rent
and rent-related costs, and workload.
Although the current law contains
provisions for adjusting fees to reflect
the rate of inflation and changes in
workload, we found that the statutorily
prescribed method for adjusting fees has
not adequately accounted for actual
growth in costs and workload during
PDUFA III. We are proposing changes to
the financial provisions of PDUFA to
correct for the shortcomings in these
adjustment factors and place FDA on a
sound financial footing so we can
continue with the program and make
enhancements to it.
1. Adjustment of Base Fee Revenue
Amount for Growth in Cost and
Workload
Section 736(b) of the PDUFA provides
the basic target fee revenue amounts
FDA uses to establish the application,
product, and establishment user fees
each year. These target fee revenue
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amounts are then adjusted for inflation
and increases in workload, and the
resulting number becomes the amount
FDA is authorized to collect in fees. The
statutory fee revenue amount for FY
2007 was $259,000,000. Adjusted for
inflation in accordance with PDUFA,
that amount became $305,455,400 for
FY 2007. However, the PDUFA IV
program will not begin until FY 2008,
so it was necessary to further adjust this
number to obtain the appropriate target
revenues for FY 2008 before any
adjustments are made.
FDA’s proposed recommendation to
Congress resulting from industry
discussions is that the base target
revenue estimate for FY 2008 should be
$392,783,000 and that this estimate
should be further adjusted for workload
for FY 2007. FDA would calculate the
workload adjustment based on
submissions through June 30, 2007, and
publish the final amount and supporting
calculations when fees for FY 2008 are
published. The proposed target revenue
estimate for FY 2008 includes the
following components:
• The base revenue amount
authorized in the current statute for FY
2007, adjusted for inflation using
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provisions of the current statute. This
amount is $305,455,400.
• An addition of $17,716,600 to
adjust the base amount for inflation for
FY 2008. We assume a continuation of
the average FDA payroll and benefit cost
inflation of 5.8 percent per year (see the
Inflation Adjustment discussion in
section II.A.2.a of this document).
• An addition of $11,721,000 to
ensure that fees cover a proportionate
share of the increased costs that FDA
will have to pay for rent and rent-related
costs and one-time costs of the required
move to the White Oak facility in Silver
Spring, MD. These costs would be
added to the fee total to maintain the
needed level of review staffing (and
associated direct costs) while also
paying for these critical
nondiscretionary operating costs.
• An addition of $20,000,000 to
adjust the base amount of fee revenues
to cover significant increases in FDA’s
drug review workload that occurred
during PDUFA III, but were not
captured by the workload adjustment
provision of PDUFA III and which we
are recommending be revised for
PDUFA IV (see the Workload
Adjustment discussion in section
II.A.2.b of this document). The PDUFA
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III workload adjuster captured workload
increases associated with increased
numbers of submissions, but did not
capture workload increases associated
with the increased level of effort for
each submission. FDA documented that
the review effort for each submission
increased significantly during PDUFA
III. The investigational new drug
workload increased markedly because of
significantly more meetings per
investigational new drug (IND)
submitted and because of a sharp
increase in the number of special
protocol assessments submitted for FDA
review.
• An addition of $37,890,000 to fund
the proposed enhancements to the
PDUFA program, including
enhancements to the premarket review
program and proposals for modernizing
and transforming the postmarket safety
system.
The sum of these components yields the
proposed target revenue figure of
$392,783,000. ($392,883,000 =
$305,455,400 + $17,716,600 +
$11,721,000 + $20,000,000 +
$37,890,000).
2. Proposed Revisions to the Inflation
Adjustment and Workload Adjustment
Applied to User Fees
(a) Inflation Adjustment: The fee
revenue amounts for PDUFA III were
stated in FY 2003 dollars and the
proposed fee revenue amounts for
PDUFA IV are stated in FY 2008 dollars.
Before fees were assessed each year in
PDUFA III, the fee revenue target was
increased and compounded based on
the higher of either: (1) The CPI/U over
the latest 12-month period or (2) the
most recent increase in pay for Federal
employees in the Washington, D.C. area,
compounded since FY 2003. The rate of
pay for employees in the Washington
D.C. area was higher in all but one year,
and the PDUFA III inflation adjustment
has resulted in average annual inflation
increases of 4.16 percent over each of
the last 5 years. However, the actual cost
of pay and benefits per full time
equivalent (FTE) is increasing faster
than this factor. Data from the past 5
years shows that the actual cost of salary
and benefits has increased at an average
rate of 5.8 percent per year during the
past 5 years for FDA. FDA proposes to
recommend changing the provision for
calculation of the inflation adjustment
to add to it a third factor—FDA’s actual
rate of increase in the costs of pay and
benefits per FTE during the most recent
5-year period—and the annual
adjustment would be based on the
highest of the three factors each year.
(b) Workload Adjustment: The
workload adjuster currently applied in
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PDUFA makes adjustments for changes
in numbers of applications, but it is
flawed in two ways. First, the surrogate
for IND workload in the current
workload adjuster is the number of new
commercial INDs submitted each year.
Since each one of these INDs is active
for several years, the number of new
applications submitted in any 1 year is
a poor surrogate for total IND workload.
Second, the workload adjuster does not
take into account increases in work
associated with active INDs, NDAs, and
BLAs. During PDUFA, there has been a
substantial increase in the numbers of
meetings and special protocol
assessments per IND submission.
However, the current workload adjuster
only takes into consideration changes in
numbers of submissions—not additional
activity required per submission. Since
FY 2002, the number of meetings per
commercial IND has increased by close
to 30 percent, and the number of special
protocol assessments is up over 90
percent. This same phenomenon occurs
with NDAs as well, but to a somewhat
lesser extent.
To remedy these flaws, the following
changes are proposed: First, we
recommend changing the surrogate for
IND workload in the statute from the
numbers of new commercial INDs
received each year to the total number
of active commercial INDs each year.
Active INDs are those that have had at
least one submission in the previous 12month period. Second, we recommend
using an adjuster applied to the
numbers of NDA/BLAs and INDs. The
proposed adjuster would adjust the
numbers of these applications in
proportion to the impact on workload of
increased meetings and special protocol
adjustments for INDs and for increased
meetings, labeling supplements, and
annual reports for NDAs and BLAs.
Under the proposed change to the
workload adjuster, we also propose to
contract with an independent
accounting firm to examine the new
adjuster and make recommendations, if
needed, for further improving this
adjuster.
technical proposals include the
following:
(a) Simplify the definition of ‘‘human
drug application’’ to include all new
drug applications under section 505(b)
of the Federal Food, Drug, and Cosmetic
Act;
(b) Amend the definition of ‘‘small
business’’ for the purpose of fee
collection to reinstate language from the
original PDUFA statute that specifies
that to qualify as a small business, the
company may not have an approved
product already introduced in or
delivered for introduction into interstate
commerce;
(c) Include capsules, tablets, and
lyophilized products as examples in the
definition of final dosage form to
provide clarification of what constitutes
a finished dosage form;
(d) Revise the waiver provisions to
clarify that the person named as the
applicant and assessed the user fee is
the person who is eligible to request a
waiver or reduction of fees;
(e) Change the date for the calculation
of the adjustment factor so it can be
calculated before the President’s budget
goes to Congress;
(f) Clarify that for fee purposes,
applications withdrawn before filing
will be treated as applications that FDA
refuses to file, and that they will be
assessed a full fee if filed again or filed
over protest;
(g) For user fee purposes, reinstate the
definition of ‘‘person’’ to include
affiliates, as enacted under FDAMA
(h) Delay offsets for collections in
excess of appropriations in any year to
the final year of the PDUFA program
and make offsetting reductions only if
cumulative fees collected over the first
4 years exceed cumulative
appropriations for fees over the same
period; and
(i) Revise the definition of
‘‘prescription drug product’’ for the
purpose of fee collection, to clarify the
exclusion of products on discontinued
product lists maintained by Center for
Drug Evaluation and Research (CDER)
and Center for Biologics Evaluation and
Research (CBER).
3. Technical Changes to Increase
Administrative Efficiency of the User
Fee Program
B. Enhancing the Process for Premarket
Review
In the premarket review area, several
changes were made in PDUFA III as
compared to PDUFA II. These are
outlined as follows:
• Continuous marketing application
pilot programs: Two pilot programs
were established under PDUFA III to
test whether providing early review of
selected applications and additional
feedback and advice to sponsors during
drug development for selected products
The FDA is proposing to recommend
several technical changes to PDUFA to
simplify some of FDA’s current
procedures, to clarify the original intent
of several PDUFA definitions, and to
remove potential ambiguity. FDA’s
analysis of the impact of these changes
indicates that they would be revenueneutral and would have a minimal
impact on industry fee-payers. These
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can further shorten drug development
and review times. Pilot 1 involved a
commitment on the part of FDA to
review and provide feedback to the
sponsor within 6 months of submission
of ‘‘reviewable units’’ of an application
in advance of the submission of the
complete application. This pilot
program represented an extension of the
‘‘rolling review’’ program begun under
FDAMA and was limited to applications
that had received a Fast Track
designation. Pilot 2 involved a
commitment on the part of FDA to
provide more structured and extensive
interaction and feedback to sponsors for
up to one Fast Track application per
review division during drug
development. This pilot represented an
extension of the usual interactions
between FDA and sponsors during drug
development. To evaluate the costs and
benefits of these pilots, FDA
commissioned an independent
assessment. The CMA Pilot 1 Evaluation
and Pilot 2 Preliminary Evaluation
Studies—Final Report is available on
the FDA Web site at https://www.fda.gov/
ope/CMA/CMAFinalReport.pdf. After
review of the findings, FDA and
industry representatives have agreed
that although the pilots demonstrated
value in some areas, the overall added
benefits of the programs did not justify
their costs to FDA. Therefore, FDA is
proposing to recommend that the CMA
pilot programs will not be continued in
PDUFA IV.
• First cycle review performance: In
PDUFA III, FDA committed to several
new goals that were focused on
improving the effectiveness and
efficiency of first cycle reviews in an
attempt to decrease the number of
multi-cycle reviews without
compromising FDA’s traditional high
standards for approval. The first new
goal was for FDA to notify the applicant
of any substantive deficiencies
identified in an application during the
initial filing review. The identification
of such deficiencies was to be
communicated to the applicant within
14 days of the 60-day application filing
date, which is commonly known as a
‘‘74 day letter.’’ FDA has consistently
met or exceeded the goals for
communication of these early
deficiencies. The second new goal was
for FDA to develop and publish a final
joint CDER/CBER guidance on GRMPs.
FDA published a final GRMP final
guidance on March 30, 2005, entitled,
‘‘Guidance for Review Staff and
Industry on Good Review Management
Principles and Practices for Prescription
Drug User Fee Act Products;
Availability,’’ at https://www.fda.gov/
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OHRMS/DOCKETS/98fr/05–6404.htm
(70 FR 16507; March 31, 2005). As part
of the goals, FDA also committed to
develop and implement a training
program for all CDER and CBER review
staff on the GRMPs. FDA met the goal
for training all review staff on the
GRMPs and has incorporated training
on the guidance as part of new reviewer
training. Finally, FDA committed to
commission an independent consultant
evaluation of the factors associated with
the conduct of first cycle reviews. The
first study was a retrospective analysis
of first cycle reviews for NME and
original BLAs submitted in FY2002–
2004, and is available on the FDA Web
site at https://www.fda.gov/ope/pdufa/
PDUFA1stCycle/pdufa1stcycle.pdf. The
second study was a prospective study of
first cycle reviews for NME and original
BLA submissions starting in FY05 and
continuing through FY07, and is
currently in progress. FDA is proposing
to recommend the continuation of first
cycle review performance initiatives.
• Independent consultants for
biotechnology clinical trial protocols:
This initiative allowed applicants for
certain biotechnology products to
request that FDA engage an independent
expert consultant, selected by FDA, to
participate in the agency’s review of the
protocol for clinical studies that were
expected to serve as the primary basis
for a claim. FDA has received no
requests under this initiative during
PDUFA III and, after discussions with
industry representatives, FDA is
proposing not to include this initiative
in the recommended PDUFA IV
program.
1. Proposed Recommendations for
Enhancement of Premarket Review
Process
In the area of premarket review, FDA
is proposing to recommend
enhancements in two areas: (1) Good
review management principles and (2)
expediting drug development.
(a) Expanding Implementation of
GRMPs: In the area of GRMPs, we are
proposing to recommend further
enhancements associated with notifying
applicants at the time of the ‘‘74-day
letter’’ of the anticipated timeline for
review of the application, including the
anticipated date for initiation of
discussions regarding product labeling
and any FDA requests for postmarketing
study commitments (PMCs).
Historically, labeling discussions have
been initiated at the late stages of a
review, often in the last week before
approval. Similarly, the agency often
communicates requests for
postmarketing commitments late in the
review cycle. Initiation of discussion of
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these important elements of the review
of an application late in the review
cycle is often due to the inability of FDA
to complete its review of the application
earlier because of an imbalance between
workload and available review staff
time. Late initiation of these important
discussions is not consistent with the
best practices that FDA has identified
and published in the GRMP guidance.
An understanding on the part of both
the reviewers and the applicant of the
process and timeline for the review
would facilitate an efficient and
scientifically sound review. FDA
believes that adhering to a timeline that
includes earlier initiation of discussion
of labeling, coupled with the new
physician labeling regulations (see
Requirements on Content and Format of
Labeling for Human Prescription Drug
and Biological Products at https://
www.fda.gov/OHRMS/DOCKETS/98fr/
06–545.pdf) (71 FR 3922, January 24,
2006), would result in clearer, more
readily understandable labeling for new
products. Furthermore, FDA believes
that initiation of discussions of possible
postmarketing commitments earlier in
the process would allow for the
commitments to be more focused on the
data needed to further inform the best
use of the products. We also expect that
earlier discussion of PMCs would help
to ensure that the agreed to studies and
study schedules are feasible, thereby
improving the timely completion of the
studies by the applicant.
The proposed recommendations
under the enhancements for GRMP are
also intended to encourage applicants to
provide FDA with applications that are
complete for review at the time of
submission. The submission of
complete applications would allow FDA
to effectively manage and adhere to its
review schedule and, ultimately, may
result in faster access to these new
products without any compromise to
FDA’s traditional high standards for
approval. Consequently, FDA believes
these proposed recommendations to be
in the best interest of the agency, the
applicant, and, ultimately, the public
health.
(b) Expediting drug development: One
of the things that the agency can do to
enhance the development of new and
beneficial drugs is to provide guidance
to industry to clarify current agency
thinking on a variety of topics
including, among other things, clinical
trial design. Our experience and insight,
gained through years of review, can help
the industry avoid wasting scarce
research and development resources on
clinical trials that are not likely to
produce results because of flawed
designs. By clarifying the agency’s
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expectations regarding the nature of
data needed to support certain types of
claims, we can allow the industry to
focus their efforts on useful trials and
decrease less useful experimentation.
This would have the benefit of
decreasing exposure of subjects to
unapproved products, decreasing the
amount of time required to bring a
beneficial new drug to market, and,
possibly, decreasing the total cost of
bringing the new drug to market, which
should translate to lower drug prices for
the consumer.
Guidance development by the agency
requires substantial time commitments
from those who are already heavily
involved in the review effort. The
PDUFA IV proposal includes increased
user fees that would be used to fund
additional staff resources to develop the
following guidances to enhance clinical
drug development (the FY dates for each
guidance represent FDA’s proposed
commitment to publish a draft guidance
on that topic by no later than the end
of FY listed):
1. Clinical Hepatotoxicity—FY 2008.
This guidance would address how to
evaluate a drug for possible
hepatotoxicity during drug development
and how FDA will review an
application to look for signs that a drug
may be a significant hepatotoxin.
2. Non-inferiority Trials—FY 2008.
This guidance would describe FDA’s
perspective on the design of
noninferiority trials. Topics addressed
are expected to include how to select
the active control, how to document the
effect size of the active control versus
placebo, and how to establish the
noninferiority margin of interest.
3. Adaptive Trial Designs—FY 2008.
This guidance would explain FDA’s
perspective on the use of adaptive trial
designs during drug development.
Topics to be addressed include the
definition of adaptive trial designs,
recommended designs, and how the
statistical issues should be addressed in
analyzing trials.
4. End of Phase 2(a) Meetings—FY
2008. This guidance would outline the
procedures and data needed for an endof-phase 2a (EOP2a) meeting. The
EOP2a meetings are intended to
facilitate FDA interactions with a
sponsor earlier in the design of the
development program to maximize the
value of the phase 2 program with the
overall goal of making drug
development more efficient and
effective.
5. Multiple Endpoints in Clinical
Trials—FY 2009. This guidance would
describe FDA’s perspective on the
appropriate procedures and analyses for
trials with multiple endpoints (e.g., a
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trial with multiple co-primary
endpoints).
6. Enriched Trial Designs—FY 2010.
This guidance would focus on
approaches to enrich the clinical trial
population to better define the efficacy
or safety of the drug under
development.
7. Imaging Standards for Use as an
End Point in Clinical Trials— FY 2011.
This guidance would focus on the use
of images as important endpoints in
controlled clinical trials. Issues would
include image acquisition, archiving,
and blinded reading.
The commitment, under this part of
the proposed PDUFA IV program,
would allow us to pursue the
development and publication of several
guidance documents to facilitate the
development of new, life-saving
therapies, moving them more efficiently
from the laboratory to the bedside.
In addition to funding the
development of guidances, under
PDUFA IV we are proposing to collect
user fees to hire additional staff to free
up reviewer time to enable greater
participation in scientific research
collaborations that will ultimately help
clarify regulatory pathways for new
technologies and potential new
biomarkers for drug safety and
effectiveness. For example, FDA intends
to participate in workshops with
representatives from the scientific
community (including industry,
academia, and other interested
stakeholders) to further the science
toward development of guidance
documents in the following areas:
1. Predictive toxicology—Emerging
science such as toxicogenomics,
proteomics, metabolomics, and
molecular imaging, is expected to yield
more sensitive, specific, and informative
tests for drug organ toxicity than the
toxicology screening techniques
currently in use. FDA reviewers will
need to participate extensively in the
design of studies intended to qualify
these new safety tests for regulatory
uses.
2. Biomarker Qualification—
Biomarkers are frequently used during
drug development to understand the
effect of a drug on biologic systems and
to predict clinical response. Before
biomarkers can be used for regulatory
decision making they must be qualified.
FDA expertise will be needed on an
ongoing basis in the effort to select and
test candidate biomarkers for
qualification. FDA reviewers will need
to participate in the design of the
definitive studies intended to qualify
the biomarker for a specific regulatory
use.
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3. Missing Data—In controlled
clinical trials it is often impossible to
ensure that every data element
described in the protocol is collected for
every study subject. For example,
subjects often discontinue participation
in a trial early and do not return for
further study visits. The question of
how to handle missing data when
analyzing the results of a trial is a very
complex one, and FDA would expect to
work in collaboration with outside
stakeholders to further explore the
science of this issue and develop
appropriate procedures.
Finally, under the proposal for
PDUFA IV, user fees would be used to
support FDA participation in workshops
and other public meetings to explore
new approaches to a structured model
for benefit/risk assessment. The results
of these interactions would be used to
assess whether pilot(s) of such new
approaches can be conducted during
PDUFA IV. These efforts may lead to the
development of guidance documents.
Under PDUFA IV, FDA proposes to
collect an additional $4,600,000 in FY
2008 and, in subsequent years, adjusted
for inflation and workload, to support at
least 20 FTEs to engage in the
collaborations with outside stakeholders
described previously.
2. Improving the IT Infrastructure for
Human Drug Review
Under PDUFA III, we agreed to
certain performance goals associated
with better management of information
technology (IT) resources and improved
consistency of IT practices across the
human drug review program. Under
PDUFA III, we centralized
accountability for PDUFA IT funding
under the Chief Information Officer
(CIO); established an IT Project
Management Office to develop and
implement processes policies, based on
the Capability Maturity Model
Integration process improvement
approach to improve software
development practices; implemented
the electronic Common Technical
Document standard for electronic
regulatory submissions; established a
common secure single point of entry for
the receipt and processing of all
electronic submissions, commonly
called the FDA Electronic Submissions
Gateway; and established a common
approach to managing desktop hardware
and software configurations. We are
now in the process of establishing a
common approach for secure e-mail that
will be implemented throughout the
PDUFA program. Following provisions
in the PDUFA III commitment letter, we
have also met quarterly with industry
representatives to discuss progress
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towards these IT goals and to address
technical implementation issues. These
accomplishments have built a strong
foundation for further progress toward
an IT environment that better serves the
human drug review program.
Under PDUFA IV, we recommend
collection of an additional $4,000,000
annually, starting in FY 2008 to enable
the agency to commit to several IT
performance goals that would move
FDA and industry towards an allelectronic environment, which would
increase the efficiency of the review
process. Under these proposed goals, we
would commit to develop a 5-year IT
plan that would lay out the technical
approach for achieving a more
integrated, standards-based electronic
regulatory submission and review
environment. The plan would help
FDA, industry, and stakeholders make
related IT investments in a more
coordinated manner. By the end of
PDUFA IV, following implementation of
these proposed goals, human drug
application sponsors would be able to
send in their electronic applications
with automated cross-links to
previously submitted data and
information, so that they only have to
submit things once. In addition, FDA
reviewers would be able to retrieve all
relevant submissions and related data
electronically from their work stations
and would have efficient tools for
searching and analyzing data to support
their reviews. These capabilities would
enable more efficient and reliable
management of regulatory submissions.
By the end of PDUFA IV, if resources
are provided as expected, we intend to
have the capability to handle two-way
transmission of regulatory
correspondence with industry, which
would accelerate the movement toward
an all-electronic submission and review
environment.
To determine whether we are moving
towards achieving the IT goals
described in PDUFA IV, we further
propose to track several key
performance indicators of the adoption
rate of electronic submissions and the
technical error rates associated with
those submissions, so that we can more
closely monitor progress toward the allelectronic environment.
Finally, in the recommended IT
performance goals for PDUFA IV, we
propose a cost-effective approach that
minimizes expenditures on existing
legacy systems and redirects those funds
toward the development of new
common systems that are better
coordinated and more flexible.
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C. Modernizing and Transforming the
Postmarket Drug Safety System
In PDUFA III, for the first time, FDA
was authorized to spend user fees
revenues to fund improvements in drug
safety. This change provided important
new resources to help improve
postmarket safety but our experience
has shown that further improvements
can be achieved. The definition of the
‘‘process for the review of human drug
applications’’ in section 735 of PDUFA
describes which products PDUFA funds
can be used for in terms of postmarket
safety review as well as the length of
time after product approval PDUFA
funds can be used for such safety
review. Specifically, 735(6)(F) states:
‘‘In the case of drugs approved after
October 1, 2002, under human drug
applications or supplements: collecting,
developing, and reviewing safety
information on the drugs, including
adverse event reports, during a period of
time after approval of such applications
or supplements, not to exceed three
years.’’
In addition, the PDUFA III
Reauthorization Performance Goals and
Procedures document stated that user
fees may be used ‘‘for a period of up to
two years post-approval for most
products and for a period of up to three
years for products that require risk
management beyond standard labeling
* * *.’’ The stated purpose of this
language was to provide user fees to
review an applicant’s implementation of
risk management plans for this period of
time and to allow for evaluation of
study reports, product use, and other
safety activities. Drug safety activities
outside of the specified timeframe were
to be funded with appropriated dollars.
As part of the PDUFA IV program, we
propose to recommend further
enhancing the program by removing the
language that limits the spending of user
fees outside of the specified timeframe.
Current data show that safety issues can
arise after a drug has been on the market
for 8 or more years. A recent FDA
analysis of safety-related label changes
made between October 2002 and August
2005, for all drug products with a
labeling change, found that the total
number of safety-related label changes
exceeded 160 changes for drugs 3 years
postapproval and remained at or above
that high level until 8 years
postapproval before starting to decline.
All stakeholders agree that the current
limitations on use of funds for
postmarketing safety-related activities
present an opportunity for improving
the agency’s ability to optimally support
adverse event surveillance, detection,
evaluation, and management. Enhancing
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the program by eliminating such
limitations would help both FDA and
drug sponsors because safety
assessments of drug products by both
FDA and sponsors are necessary for
drugs over time to adequately manage
risks, regardless of approval date.
Increased resources, including from
PDUFA funds, would enable FDA to
engage in safety review activities, such
as studies of drugs in the same class
approved before and after October 1,
2002, to adequately assess significant
drug safety issues. The current
description of postmarketing safety
activities in the definition of the
‘‘process for the review of human drug
applications’’ could also be revised to
better reflect the broad variety of
activities that are important to
postmarket safety review.
As part of the reauthorization of
PDUFA, FDA proposes changing the
statute to eliminate the statutory
restrictions so that PDUFA fees could be
used to assess safety issues
postapproval, independent of a
product’s approval date and would
allow the agency to review the drug’s
safety in whatever time frame risks arise
using all available resources. This
change would provide much needed
support for timely, predictable,
consistent, and scientifically sound
regulatory decisionmaking and would
work towards a fully integrated
evaluation of drugs and biologics
throughout their life cycle.
In addition, we propose expanding
the description of postmarket safety
activities to capture a broader range of
activities related to postmarket safety
review. For example, FDA would use
$29,290,000 in new user fee funds to
enhance and modernize the current U.S.
drug safety system. We would adopt
new scientific approaches, improve the
utility of existing tools for the detection,
evaluation, prevention, and mitigation
of adverse events associated with drugs
and biological products. In addition,
FDA would use these funds to continue
to enhance and improve communication
and coordination between pre- and
postmarket review staff. Potential
activities in this area might include
integration of certain proposed
recommendations made by the Institute
of Medicine (IOM) in their September
2006 report entitled, ‘‘The Future of
Drug Safety: Promoting and Protecting
the Health of the Public.’’
PDUFA IV funds would also be used
to support a number of activities
designed to modernize the process of
pharmacovigilance. One key initiative
would be the implementation of an FDA
contract to one or more outside research
organization(s) to conduct research on
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determining the best way to maximize
the public health benefits associated
with collecting and reporting serious
and nonserious adverse events
occurring throughout a product’s life
cycle. Studies under this contract would
answer such central questions as the
number and types of safety concerns
that are discovered by various types of
adverse event collection, the age of the
medical products at the time such safety
concerns are detected, and the types of
actions that are subsequently taken and
their ultimate effect on patient safety.
PDUFA IV funds would also support
the development of a guidance
document to delineate epidemiology
best practices. Epidemiologic studies
using large automated databases are
increasingly being performed to
evaluate drug safety. These studies and
safety analyses are complex and employ
a variety of nonstandardized analytic
methods and assumptions. During the
course of PDUFA IV, FDA, with input
from academia, industry, and others
from the general public, would hold a
public workshop to identify best
practices in this emerging field,
ultimately developing a document that
addresses epidemiology best practices
and provides guidance on how to carry
out scientifically sound observational
studies using quality data resources.
Another critical part of the
transformation of the drug safety
program would be maximizing the
usefulness of tools used for adverse
event detection and risk assessment. To
achieve this end, data other than
spontaneous adverse event reports,
including population-based
epidemiological data and other types of
observational data resources, would be
used and evaluated. Access to these
types of data would expand our
capability to carry out targeted
postmarketing surveillance, look at class
effects of drugs, and potentially carry
out signal detection using data resources
other than reports from FDA’s adverse
event reporting system (AERS). PDUFA
IV funds would be used to obtain access
to additional databases and increase
program staffing with epidemiologists,
safety evaluators, and programmers who
can use these new resources.
As mentioned previously, the PDUFA
III Reauthorization Performance Goals
and Procedures document provided user
fees to review implementation of a risk
management plans for a limited period
of time and to allow for evaluation of
study reports, product use, and other
safety activities. Risk communication
and management have now become a
routine part of human drug review, yet
many of the risk management and risk
communication tools the industry uses
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remain unproven and unstandardized.
To promote more effective and
consistent use of these tools to mitigate
the risk of drugs and biological
products, under PDUFA IV, with input
from academia, industry, and others
from the general public, we would
conduct an annual systematic public
discussion and review of the
effectiveness of one to two risk
management programs and one major
risk management tool per year. Reports
from these discussions would be posted
on the FDA Web site.
FDA would also use PDUFA IV fees
to enhance the agency’s AERS and
surveillance tools, to strengthen its IT
infrastructure to support access and
analyses of externally linked databases,
and to support a safety workflow
tracking system. This support for drug
and biological product safety-related IT
systems is critical to ensure the best
collection, evaluation, and management
of the vast quantity of safety data
received by FDA.
FDA would use PDUFA IV funds to
develop and periodically update a 5year plan describing the range of
activities designed to enhance and
modernize the drug safety system. FDA
would publish and seek public
comment on an initial plan for these
activities and conduct an annual
assessment of progress against the plan
to be published on FDA Web site. In
addition to progress against the specific
modernization activities described
previously, the annual report would
include an update on FDA efforts to
facilitate the interactions between the
Office of New Drugs and the Office of
Surveillance and Epidemiology related
to the process of evaluating and
responding to postmarketing drugs
safety/adverse event reports. FDA
would publish updates to the
modernization plan as FDA deems
necessary and post on FDA’s Web site
draft revisions to the plan, soliciting
comments from the public on those
draft revisions and then carefully
considering all public comments before
completing and publishing updates to
the plan.
Another recent study by the IOM,
entitled ‘‘Preventing Medication Errors:
Quality Chasm Series,’’ (July 20, 2006),
estimates that, on average, every
hospitalized patient is subject to at least
one medication error per day. These
errors lead to costly morbidity and
mortality. The IOM concluded that drug
names that look or sound similar, in
addition to the layout and presentation
of important drug information on the
label, labeling, and packaging of drug
products increase the risk of medication
errors. The IOM report recommended
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1751
that the FDA, the pharmaceutical
industry, and other stakeholders should
collaborate in several areas to improve
methods for naming and labeling drug
products and communicating
medication information to providers
and consumers and advised the FDA to
develop guidance documents for
industry related to drug naming,
labeling, and packaging.
Using PDUFA IV funds, FDA would
implement various measures to reduce
medication errors related to look-alike
and sound-alike proprietary names as
well as factors such as unclear label
abbreviations, acronyms, dose
designations, and error-prone label and
packaging designs. Activities to be
funded include guidance development,
review performance goals, and initiation
of a pilot program to explore a different
paradigm for proprietary name review.
Fees would provide the resources
FDA needs to publish three guidances to
industry: (1) Guidance on the contents
of a complete submission package for a
proposed proprietary drug/biological
product name; (2) guidance on best
practices for naming, labeling, and
packaging drugs and biologics to reduce
medication errors; and (3) guidance on
proprietary name evaluation best
practices. These guidances, developed
after consultation with industry,
academia, and others from the general
public, would provide a scientifically
sound and consistent approach to the
selection, evaluation, and review of
proprietary names and would also
create a framework for best practices for
the layout and design of drug labels and
packaging to prevent or minimize
medication errors.
In addition, under the proposed
PDUFA IV program, FDA would commit
to a performance goal of 180 days for
reviewing proprietary names submitted
during the IND and NDA phases. For
submissions received as part of an IND,
submitted as early as the end of phase
2 of drug development, FDA would
increase the percentage of submissions
subject to this goal, from 50 percent in
year 1 to 90 percent in year 4 of the
program. In a similar phased-in fashion,
for submissions received as part of an
NDA or BLA, FDA would review 50
percent (in year 1) increasing to 90
percent (in year 4) of proprietary name
submissions within 90 days of receipt.
Commitment to review goals would
enhance the timeliness and
predictability of proprietary name
review.
During PDUFA IV, FDA proposes to
develop and implement a pilot program
that shifts the responsibility for testing
proposed proprietary names from FDA
to the pharmaceutical industry. This
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program would enable pharmaceutical
firms participating in the pilot to
evaluate proposed proprietary names
and submit the data generated from
those evaluations to FDA for review
prior to approval. Using this more
traditional FDA review role was
recommended by the IOM in November
1999 report, entitled ‘‘To Err Is Human:
Building a Safer Health System, ’’ as
well as the HHS Advisory Committee on
Regulatory Reform in November of 2002
Secretary’s Advisory Committee on
Regulatory Reform, November 21, 2002,
https://regreform.hhs.gov/meetinginfo/
november_meetinginfo.htm. The
proposed pilot would allow this
approach to be evaluated for its
contribution to the efficiency and
timeliness of proprietary name review.
III. What We Are Proposing to
Recommend for Review of Direct-ToConsumer Advertising
In addition to our proposed
recommendations for enhancements to
the current human drug review
program, we are proposing to
recommend a program separate from,
but related to, PFUFA assessing fees for
advisory reviews of DTC television
advertisements. Research has shown
there can be benefits associated with
DTC prescription drug television
advertising, such as informing patients
about the availability of new treatment
options and encouraging patients to see
a physician about an illness for the first
time. Notwithstanding these benefits,
concerns have arisen about the effects of
DTC television advertisements on
prescribing practices and prescription
drug use. Companies have the option of
submitting their proposed
advertisements to FDA for advisory
review before publicly disseminating
them, which gives them with the benefit
of FDA input on whether or not the
advertisements are accurate, balanced,
and adequately supported, enabling
them to address any problems before the
advertisements are shown to the public,
thus improving the quality of the
advertisements.
Companies recognize the benefits this
advisory review mechanism offers. In
fact, PhRMA recently stated in its
voluntary guidance principles on DTC
advertising that companies should
submit all new DTC television
advertisements to FDA before
broadcasting them https://
www.phrma.org/files/
DTCGuidingprinciples.pdf. However,
although FDA’s DTC advisory review
workload has been steadily increasing,
staffing for this activity has remained
level. As a result, it is impossible for
FDA to review all of the DTC television
advertisement advisory submissions it
receives in a timely manner. The lack of
timely, predictable FDA review times
for DTC television advertisements is
detrimental to companies’ ability to
accurately set timeframes for their
marketing campaigns and discourages
companies from submitting these
materials for advisory review.
We propose creating a separate
program, not directly included under
PDUFA IV, to assess, collect, and use
fees for the advisory review of
prescription drug television
advertisements. These user fees would
not be funded by application, product,
or establishment fees assessed under
PDUFA. Instead, these new fees would
be assessed separately and collected
only from those companies that intend
to seek FDA advisory reviews of DTC
television advertisements. The proposed
recommendation for fee funding and the
estimated number of supported staff are
summarized in table 2 of this document.
TABLE 2.—PROPOSED FEES FOR DTC ADVERTISEMENT REVIEW (STARTING IN FY 2008)
Proposed Program
Dollars
FTE
$6,250,000
27
Program Total (in FY 2008)
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Advisory Review of DTC Television
Advertisements
$6,250,000
27
This program would provide for
increased FDA resources to allow for the
timely review of DTC television
advertisement advisory submissions. To
ensure stable funding for the program in
case the number of advisory
submissions fluctuates widely from year
to year, the program would assess a onetime participation fee. The program
would then charge fees each year for
each advisory review requested. These
new fees would provide sufficient
resources for FDA to hire additional
staff to review DTC television advisory
submissions in a predictable, timely
manner. FDA anticipates collecting
$6.25 million in annual fees during the
first year of the program (and a similar
amount to go into the reserve fund) to
support 27 additional staff to review
DTC television advertising. Advisory
review fee amounts would be adjusted
annually for inflation and to take into
account increases in workload. As part
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of this program, FDA is proposing to
commit to certain performance goals
including review of a certain number of
original advisory review submissions in
45 days and resubmissions in 30 days.
The goals would be phased in over the
5 years of the program to allow for
recruitment and training of staff.
IV. What Information Should You
Know About the Meeting?
A. When and Where Will the Meeting
Occur? What Format Will We Use?
Through this document, we are
announcing the convening of a public
meeting to hear stakeholder views on
the recommendations we propose to
provide to Congress on the
reauthorization of PDUFA IV.
We will conduct the meeting on
February 16, 2007, at the Grand Hyatt
Washington at Washington Center (see
ADDRESSES). In general, the meeting
format will include presentations by
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FDA and a series of panels representing
different stakeholder interest groups
(such as patient advocates, consumer
advocates, industry, health
professionals, and academic
researchers). We will also give
individuals the opportunity to make
presentations at the meeting, and for
organizations and individuals to submit
written comments to the docket after the
meeting.
B. How Do You Register for the Meeting
or Submit Comments?
If you wish to attend and/or make a
presentation at the meeting, please send
an electronic mail message to
CBERTrainingSuggestions@fda.hhs.gov
by February 2, 2007. Your e-mail should
include the following information:
Name, Company, Company Address,
Company Phone Number, and E-mail
Address. You will receive a
confirmation within 2 business days.
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We also will accept walk-in
registration at the meeting site, but
space is limited, and we will close
registration when maximum seating
capacity (approximately 500) is reached.
We will try to accommodate all
persons who wish to make a
presentation. The time allotted for
presentations may depend on the
number of persons who wish to speak
Additionally, regardless of whether
you wish to make a presentation or
simply attend the meeting, please notify
us if you need any special
accommodations (such as wheelchair
access or a sign language interpreter).
If you would like to submit comments
regarding these proposed
recommendations, please send your
comments to the Division of Dockets
Management (see ADDRESSES). Submit a
single copy of electronic comments or
two paper copies of any written
comments, except that individuals may
submit one paper copy. Comments are
to be identified with the docket number
found in brackets in the heading of this
document. Received comments may be
seen in the Division of Dockets
Management between 9 a.m. and 4 p.m.,
Monday through Friday.
To ensure consideration of your
comments, you should send your
comments no later than February 23,
2007.
C. Will Meeting Transcripts Be
Available?
We will prepare a meeting transcript
and make it available on our Web site
(www.fda.gov) after the meeting. We
anticipate that transcripts will be
available approximately 30 business
days after the meeting. The transcript
will also be available for public
examination at the Division of Dockets
Management (HFA–305), 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852,
between 9 a.m. and 4 p.m. Monday
through Friday.
Dated: January 10, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 07–122 Filed 1–11–07; 8:45 am]
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Substance Abuse and Mental Health
Services Administration
Current List of Laboratories Which
Meet Minimum Standards To Engage in
Urine Drug Testing for Federal
Agencies
Substance Abuse and Mental
Health Services Administration, HHS.
ACTION: Notice.
AGENCY:
SUMMARY: The Department of Health and
Human Services (HHS) notifies Federal
agencies of the laboratories currently
certified to meet the standards of
Subpart C of the Mandatory Guidelines
for Federal Workplace Drug Testing
Programs (Mandatory Guidelines). The
Mandatory Guidelines were first
published in the Federal Register on
April 11, 1988 (53 FR 11970), and
subsequently revised in the Federal
Register on June 9, 1994 (59 FR 29908),
on September 30, 1997 (62 FR 51118),
and on April 13, 2004 (69 FR 19644).
A notice listing all currently certified
laboratories is published in the Federal
Register during the first week of each
month. If any laboratory’s certification
is suspended or revoked, the laboratory
will be omitted from subsequent lists
until such time as it is restored to full
certification under the Mandatory
Guidelines.
If any laboratory has withdrawn from
the HHS National Laboratory
Certification Program (NLCP) during the
past month, it will be listed at the end,
and will be omitted from the monthly
listing thereafter.
This notice is also available on the
Internet at https://workplace.samhsa.gov
and https://www.drugfreeworkplace.gov.
FOR FURTHER INFORMATION CONTACT: Mrs.
Giselle Hersh or Dr. Walter Vogl,
Division of Workplace Programs,
SAMHSA/CSAP, Room 2–1035, 1 Choke
Cherry Road, Rockville, Maryland
20857; 240–276–2600 (voice), 240–276–
2610 (fax).
SUPPLEMENTARY INFORMATION: The
Mandatory Guidelines were developed
in accordance with Executive Order
12564 and section 503 of Public Law
100–71. Subpart C of the Mandatory
Guidelines, ‘‘Certification of
Laboratories Engaged in Urine Drug
Testing for Federal Agencies,’’ sets strict
standards that laboratories must meet in
order to conduct drug and specimen
validity tests on urine specimens for
Federal agencies. To become certified,
an applicant laboratory must undergo
three rounds of performance testing plus
an on-site inspection. To maintain that
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1753
certification, a laboratory must
participate in a quarterly performance
testing program plus undergo periodic,
on-site inspections.
Laboratories which claim to be in the
applicant stage of certification are not to
be considered as meeting the minimum
requirements described in the HHS
Mandatory Guidelines. A laboratory
must have its letter of certification from
HHS/SAMHSA (formerly: HHS/NIDA)
which attests that it has met minimum
standards.
In accordance with Subpart C of the
Mandatory Guidelines dated April 13,
2004 (69 FR 19644), the following
laboratories meet the minimum
standards to conduct drug and specimen
validity tests on urine specimens:
ACL Laboratories, 8901 W. Lincoln
Ave., West Allis, WI 53227, 414–328–
7840 / 800–877–7016 (Formerly:
Bayshore Clinical Laboratory).
ACM Medical Laboratory, Inc., 160
Elmgrove Park, Rochester, NY 14624,
585–429–2264.
Advanced Toxicology Network, 3560
Air Center Cove, Suite 101, Memphis,
TN 38118, 901–794–5770 / 888–290–
1150.
Aegis Analytical Laboratories, Inc., 345
Hill Ave., Nashville, TN 37210, 615–
255–2400.
Baptist Medical Center-Toxicology
Laboratory, 9601 I–630, Exit 7, Little
Rock, AR 72205–7299, 501–202–2783
(Formerly: Forensic Toxicology
Laboratory Baptist Medical Center).
Clinical Reference Lab, 8433 Quivira
Road, Lenexa, KS 66215–2802, 800–
445–6917.
Diagnostic Services, Inc., dba DSI,
12700 Westlinks Drive, Fort Myers,
FL 33913, 239–561–8200 / 800–735–
5416.
Doctors Laboratory, Inc., 2906 Julia
Drive, Valdosta, GA 31602, 229–671–
2281.
DrugScan, Inc., P.O. Box 2969, 1119
Mearns Road, Warminster, PA 18974,
215–674–9310.
Dynacare Kasper Medical Laboratories*,
10150–102 St., Suite 200, Edmonton,
Alberta, Canada T5J 5E2, 780–451–
3702 / 800–661–9876.
ElSohly Laboratories, Inc., 5 Industrial
Park Drive, Oxford, MS 38655, 662–
236–2609.
Gamma-Dynacare Medical
Laboratories*, A Division of the
Gamma-Dynacare Laboratory
Partnership, 245 Pall Mall Street,
London, ONT, Canada N6A 1P4,
519–679–1630.
Kroll Laboratory Specialists, Inc. , 1111
Newton St., Gretna, LA 70053, 504–
361–8989 / 800–433–3823 (Formerly:
Laboratory Specialists, Inc.).
E:\FR\FM\16JAN1.SGM
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Agencies
[Federal Register Volume 72, Number 9 (Tuesday, January 16, 2007)]
[Notices]
[Pages 1743-1753]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 07-122]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2007N-0005]
Prescription Drug User Fee Act; Public Meeting
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public meeting.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, we) is publishing
proposed recommendations for the reauthorization of the Prescription
Drug User Fee program for the process of human drug application review
for fiscal years (FY) 2008 to 2012. These proposed recommendations were
developed after discussions with regulated industry and consultation
with appropriate scientific and academic experts, healthcare
professionals, and representatives of patient and consumer advocacy
groups. Section 505 of the Public Health Security and Bioterrorism
Preparedness and Response Act of 2002, enacted June 12, 2002, directs
FDA to publish these proposed recommendations in the Federal Register;
hold a meeting at which the public may present its views on such
recommendations; and provide for a period of 30 days for the public to
provide written comments on such recommendations.
DATES: The public meeting will be held on February 16, 2007, from 9
a.m. to 5 p.m. Submit written comments by February 23, 2007.
Registration to attend the meeting must be received by February 2,
2007.
ADDRESSES: The meeting will be held at the Grand Hyatt Washington at
Washington Center, 1000 H St. NW., Washington, DC 20001. Located at the
Metro Center metro stop. Follow 11th St. exit to the lobby of the Grand
Hyatt. For additional directions, see the hotel Web site at: https://
grandwashington.hyatt.com/hyatt/hotels/.
Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit electronic comments to https://www.fda.gov/
dockets/ecomments.
FOR FURTHER INFORMATION CONTACT:
For information regarding this document, contact: Ann Sullivan,
Office of Policy and Planning (HFP-20), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-827-5887, FAX: 301-827-
5225, e-mail: Ann.Sullivan@fda.hhs.gov.
For information regarding registration, contact: Bernadette
Kawaley, Office of Communication, Training and Manufacturers Assistance
(HFM-49), Food and Drug Administration, Center for Biologics Evaluation
and Research, 1401 Rockville Pike, suite 200N, Rockville, MD 20852,
301-827-2000, FAX: 301-827-3079.
SUPPLEMENTARY INFORMATION:
I. Introduction
The Prescription Drug User Fee Act (PDUFA I), first enacted in 1992
(Public Law 102-571, October 29, 1992), authorized FDA to collect user
fees from regulated industry that were to be dedicated to expediting
the review of human drug applications in accordance with certain
performance goals identified in letters from the Secretary of Health
and Human Services to the Chairman of the Energy and Commerce Committee
of the House of Representatives and the Chairman of the Labor and Human
Resources Committee of the Senate (138 Cong. Rec. H9099-H9100 (daily
ed. September 22, 1992)). In 1997, as PDUFA I expired, Congress passed
the Food and Drug Administration Modernization Act (FDAMA, Public Law
105-115). FDAMA included, among other things, an extension of PDUFA
(PDUFA II) for an additional 5 years. In 2002, Congress extended PDUFA
again for 5 years (PDUFA III) through the Public Health
[[Page 1744]]
Security and Bioterrorism Preparedness and Response Act (Public Law
107-188).
Before PDUFA, FDA's review process was more unpredictable, and
slower. At the same time, regulators in other countries were able to
review products faster. Access to new medicines for U.S. patients
lagged behind. For example, a 1989 study by researchers at Tufts
University, analyzing differences in the number of new drugs introduced
and time to marketing in the United Kingdom compared to the United
States for the period 1977 to 1987, found that the United Kingdom led
the United States in the number of first introductions of new drugs
(114 versus 41) and in the average lead time for mutually available
drugs (60.7 months lead time in the United Kingdom versus 28.9 months
in the United States) and in the number of exclusively available new
drugs (70 versus 54).\1\ In addition, a 1992 review of the
international literature related to drug lag found that most studies
reported the United States, Sweden and Norway to have a long delay in
the introduction of new drugs, while the United Kingdom and (West)
Germany were generally found to have the shortest delay.\2\ Chronic
understaffing of drug review and related delays in U.S. patient access
to new drugs led to the 1992 enactment of PDUFA. PDUFA provided FDA
with added funds that enabled the agency to hire additional reviewers
and support staff and upgrade its information technology systems to
speed the application review process for new drugs and biological
products without compromising FDA's high standards for approval.
---------------------------------------------------------------------------
\1\ Kaitin, K.I., N. Mattison, F.K. Northington, L. Lasagna, The
drug lag: an update of new drug introductions in the United States
and in the United Kingdom, 1977 through 1987,Clinical Pharmacology
and Therapeutics, 1989; 46 (2):121-38.
\2\ Andersson, F., The drug lag issue: the debate seen from an
international perspective, International Journal of Health Services,
1992; 22(1): 53-72.
---------------------------------------------------------------------------
Since the beginning of the PDUFA program, there has been a
significant improvement in FDA funding for the drug review program,
including significant investments in information technology. PDUFA has
enabled FDA to virtually double the staff dedicated to the process of
reviewing human drug applications since 1992.
Under PDUFA, the industry provides additional funds through user
fees that are available to FDA, in addition to appropriated funds, to
spend on the human drug review process. Our authority to collect user
fees is ``triggered'' only when a base amount of appropriated funds,
adjusted for inflation, is spent.
In conjunction with PDUFA, FDA set review performance goals that
became more stringent each year. These goals applied to the review of
original new human drug and biological product applications,
resubmissions of original applications, and supplements to approved
applications. During the first few years of PDUFA I, we eliminated
backlogs of original applications and supplements that had formed in
earlier years when the program had fewer resources. Phased in over the
5 years of PDUFA I, the goals were to review and act on 90 percent of
priority new drug applications (NDAs), biologics license applications
(BLAs), and efficacy supplements (i.e., submissions for products
providing significant therapeutic gains) within 6 months of submission
of a complete application; to review and act on 90 percent of
nonpriority original NDAs, BLAs, and efficacy supplements within 12
months, and on resubmissions and manufacturing supplements within 6
months. Over the course of PDUFA I, we exceeded all of these
performance goals.
Under PDUFA II, some review performance goals continued to shorten.
For example, by 2002, the PDUFA II goals called on us to review and act
on 90 percent of the following:
Standard new drug and biological product applications and
efficacy supplements within 10 months,
Chemistry and manufacturing control supplements requiring
prior FDA approval within 4 months, and
Class 1 resubmissions (that respond to relatively minor
deficiencies such as labeling changes) within 2 months.
In addition, PDUFA II added a new set of goals intended to improve
our interactions with industry sponsors during the early years of drug
development, again with the goal of making promising new drug therapies
available to patients sooner. For example, these procedural goals
called for us to meet with sponsors and provide followup meeting
minutes within a certain number of days, and provide responses to
questions on industry submitted special study protocols within a
certain number of days. For example, PDUFA II goals called for us to
respond to 90 percent of industry requests:
Scheduling Type A meetings within 30-calendar days of FDA
receipt of the meeting request,
Scheduling Type B meetings within 60-calendar days of FDA
receipt of the meeting request,
Scheduling Type C meetings within 75-calendar days of FDA
receipt of the meeting request, and
Completing written assessments of the adequacy of special
protocols within 45 days of sponsor requests.
However, the agency experienced a much heavier review workload than
was accounted for by PDUFA II fee funding. By the end of PDUFA II, the
program was beginning to falter in terms of both performance and
financial stability. Although we were able to meet the letter of the
performance deadlines in many cases, FDA reviewers were not able to
allocate time for earlier and more frequent communication and feedback
to sponsors that might have resulted in better-quality applications and
a higher rate of first-cycle approvals.
Under the current program, reauthorized in 2002 (PDUFA III),
additional money from user fees was authorized to better finance the
expanded scope and growing volume of demand for FDA review and
consultation, and a mechanism was placed in PDUFA to annually adjust
fee revenues for increases in workload associated with the process for
the review of human drugs. For the first time, PDUFA III also
authorized FDA to spend user fee funds on certain aspects of postmarket
risk management. The review performance and procedural goals associated
with PDUFA III were similar to those under PDUFA II for FY 2002
performance levels, but the PDUFA III program addressed drug safety
issues and established several new initiatives to improve application
submissions and agency-sponsor interactions during drug development and
application review. The goals under PDUFA III included new provisions,
for example, to develop guidance for industry on good risk assessment,
risk management, and pharmacovigilance practices; to fund outside
expert consultants to help evaluate and improve review management
processes; and to centralize accountability and funding for all PDUFA
information technology initiatives and activities.
Furthermore, in conjunction with PDUFA's reauthorization in 2002,
FDA set the goal of creating a guidance for our review staff and
industry on good review management principles and practices (GRMPs) as
they apply to the first cycle review of NDAs, BLAs, and efficacy
supplements. We also set a goal of evaluating whether providing early
review of selected applications and additional feedback and advice to
sponsors during drug development for selected products can shorten drug
development and review times. Two ``continuous marketing application''
[[Page 1745]]
(CMA) pilot programs were initiated. CMA Pilot 1 provides for the
review of a limited number of presubmitted portions of NDAs and BLAs.
Under CMA Pilot 2, FDA and applicants can enter into agreements to
engage in frequent scientific feedback and interactions during the
investigational new drug phase of product development.
When it enacted PDUFA III, Congress enacted special provisions
regarding public accountability in the development of recommendations
for PDUFA IV. Congress directed FDA, when developing recommendations to
the Congress for PDFUA IV, to ``consult with the Committee on Energy
and Commerce of the House of Representatives, the Committee on Health,
Education, Labor, and Pensions of the Senate, appropriate scientific
and academic experts, health care professionals, representatives of
patient and consumer advocacy groups, and the regulated industry''
(Section 505. Accountability and Reports).
In preparing our proposed recommendations for PDUFA
reauthorization, we have conducted technical discussions with regulated
industry and have consulted with stakeholders as required by law. We
began our public consultation on PDUFA reauthorization with a public
meeting held on November 14, 2005 ( https://www.fda.gov/OHRMS/DOCKETS/
98fr/05-20875.htm).
The meeting included presentations by FDA and a series of panels
representing different stakeholder groups, including patient advocates,
consumer groups, regulated industry, health professionals and academic
researchers. The stakeholders were asked to respond to the following
questions: (1) What is your assessment of the overall performance of
the PDUFA program thus far and (2) What aspects of PDUFA should be
retained, or what should be changed, to further strengthen and improve
the program?
There was general agreement among the responding stakeholders that
PDUFA should be reauthorized. Most expressed the view that drug review
should not only include safety and effectiveness review prior to
marketing approval, but also should encompass continued safety
monitoring after approval. Many panelists supported increased PDUFA
funds for postmarket drug safety surveillance, including developing and
monitoring risk management tools. A number of panelists also expressed
support for increased resources to fund the review of direct-to-
consumer (DTC) advertising. Some panelists expressed concern that over-
emphasizing safety might delay patient access to new treatments, and
some expressed support for PDUFA funding of ``Critical Path'' projects
to help speed new drug development (see https://www.fda.gov/oc/
initiatives/criticalpath/).
In addition to our initial public meeting in November 2005, we held
followup meetings to obtain further input on the PDUFA program and
suggestions regarding what features should be proposed or amended with
program reauthorization.
On May 22, 2006, we held a meeting with patient advocacy groups.
Overall, these groups supported reauthorization of PDUFA as a vehicle
for speeding patient access to safe and effective drug therapies. They
also suggested that user fees be increased to sufficiently fund
postmarket safety activities and that the issues raised in the March
2006 GAO report entitled, ``Drug Safety: Improvement Needed in FDA's
Postmarket Decision-making and Oversight Process'' (GAO-06-402) https://
www.gao.gov/new.items/d06402.pdf report on drug safety be addressed. In
addition, it was suggested that FDA establish postmarket performance
goals, such as milestones for development of a better postmarket safety
system.
On May 23, 2006, FDA held a meeting with consumer advocacy groups
to get their input on PDUFA reauthorization. Some consumer groups
indicated a preference for full funding of human drug review with
appropriated funds rather than user fees, but they generally considered
fee-funding to be inevitable and PDUFA reauthorization to be necessary.
Given this, the consumer advocacy groups who participated in the
meeting emphasized that user fees should be used to enable the agency
to adequately cover its priorities, but there should be no ties between
user fees and performance goals. They also expressed the view that
appropriated funding should be increased and there should be increased
funding to enhance FDA's capacity for postmarket safety and DTC
advertising review. Some consumer advocates further suggested that FDA
charge separate fees for DTC advertising review.
On June 23, 2006, we held a meeting with health professional groups
to obtain their views and suggestions for reauthorization. The health
professional groups supported PDUFA reauthorization to maintain an
efficient process and the availability of safe and effective new drugs
on the market. They also thought sufficient funding was needed to
maintain a competent scientific staff. The health professional groups
thought PDUFA fees should be increased to support safety surveillance
and risk management, and the current statutory time period for using
fee funds for safety-related work should be eliminated or expanded.
They also felt that fee-funded support for risk management plans should
be expanded to include older drugs as well as those recently approved.
They indicated that the issues raised in the March 2006 GAO report on
drug safety needed to be addressed. Finally, they suggested that PDUFA
funds be increased to support the review of DTC advertising.
Congress also directed FDA to publish in the Federal Register the
proposed recommendations developed through this process after
negotiations with the regulated industry, present the proposed
recommendations to the congressional committees specified in the
statute, hold a public meeting at which the public can present its
views on the proposed recommendations, and provide for a period of 30
days for the public to provide written comment on the proposed
recommendations.
We have now concluded discussions with industry and other
stakeholders regarding reauthorization of PDUFA. The purpose of this
document is to publish the recommendations we intend to propose to
Congress and announce the dates for the upcoming public meeting and
written comment period. After the public meeting and the close of the
30-day comment period, we plan to undertake a careful review of all
public comments on these proposed recommendations.
II. What We Are Proposing to Recommend for PDUFA IV
For PDUFA IV, as described in the following paragraphs, we plan,
with a few exceptions, to carry forward the performance goals from
PDUFA III and we propose additional goals related to proposed
enhancements to the program. Our proposed recommendations fall into
three major categories: (1) Proposals to ensure sound financial footing
for the human drug review program; (2) proposals to enhance the process
for premarket review of human drug applications; and (3) proposals to
modernize and transform the postmarket safety system. In addition, we
are proposing to recommend a program separate from, but related to,
PDUFA pertaining to fees assessed for advisory reviews of DTC
television advertisements. The summary table containing the proposals
and related fees under PDUFA IV can be found in table 1 of this
document. The discussion and additional fee estimates in this section
(II) and table 1 of this document,
[[Page 1746]]
do not include our proposals and proposed fee revenue figures for
review of DTC television advertisements. Those proposals are provided
in section III of this document.
Table 1.-- PDUFA IV Financial Baseline and Enhancements (starting in FY 2008)
----------------------------------------------------------------------------------------------------------------
Financial Baseline Dollars FTE
----------------------------------------------------------------------------------------------------------------
FY 2007 Baseline-- $305,455,400 1539
Adjusted for
Inflation
----------------------------------------------------------------------------------------------------------------
Inflation $17,716,600 .............................................
Adjustment for FY
2008
----------------------------------------------------------------------------------------------------------------
Adjustment for $11,721,000 .............................................
Increased Rent
and Rent-Related
Costs
----------------------------------------------------------------------------------------------------------------
Adjustment for $20,000,000 87
Increased Work
per IND & NDA
PDUFA III
================================================================================================================
PDUFA IV Baseline $354,893,000 1626
Before
Enhancements
----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------
Enhancements
----------------------------------------------------------------------------------------------------------------
Premarket--Expedit $4,600,000 20
ing Drug
Development
----------------------------------------------------------------------------------------------------------------
Premarket--Improvi $4,000,000 .............................................
ng IT
Infrastructure
for Drug Review
----------------------------------------------------------------------------------------------------------------
Postmarket--Modern $29,290,000 82
izing and
Transforming
Safety System
================================================================================================================
PDUFA IV Total\1\ $392,783,000 1728
(in FY 2008)
----------------------------------------------------------------------------------------------------------------
\1\Further workload adjustment, to account for work levels in FY 2007, is expected to add about $45,000,000 and
195 FTEs for a final total of about $437,800,000 and 1923 FTEs for FY 2008.
A. Proposed Recommendations to Ensure Sound Financial Footing
Although user fees have provided substantial resources to FDA since
the beginning of the program, user fees have not kept up with the
increasing costs of the program associated with inflation in pay and
benefit costs to the agency, rent and rent-related costs, and workload.
Although the current law contains provisions for adjusting fees to
reflect the rate of inflation and changes in workload, we found that
the statutorily prescribed method for adjusting fees has not adequately
accounted for actual growth in costs and workload during PDUFA III. We
are proposing changes to the financial provisions of PDUFA to correct
for the shortcomings in these adjustment factors and place FDA on a
sound financial footing so we can continue with the program and make
enhancements to it.
1. Adjustment of Base Fee Revenue Amount for Growth in Cost and
Workload
Section 736(b) of the PDUFA provides the basic target fee revenue
amounts FDA uses to establish the application, product, and
establishment user fees each year. These target fee revenue amounts are
then adjusted for inflation and increases in workload, and the
resulting number becomes the amount FDA is authorized to collect in
fees. The statutory fee revenue amount for FY 2007 was $259,000,000.
Adjusted for inflation in accordance with PDUFA, that amount became
$305,455,400 for FY 2007. However, the PDUFA IV program will not begin
until FY 2008, so it was necessary to further adjust this number to
obtain the appropriate target revenues for FY 2008 before any
adjustments are made.
FDA's proposed recommendation to Congress resulting from industry
discussions is that the base target revenue estimate for FY 2008 should
be $392,783,000 and that this estimate should be further adjusted for
workload for FY 2007. FDA would calculate the workload adjustment based
on submissions through June 30, 2007, and publish the final amount and
supporting calculations when fees for FY 2008 are published. The
proposed target revenue estimate for FY 2008 includes the following
components:
The base revenue amount authorized in the current statute
for FY 2007, adjusted for inflation using provisions of the current
statute. This amount is $305,455,400.
An addition of $17,716,600 to adjust the base amount for
inflation for FY 2008. We assume a continuation of the average FDA
payroll and benefit cost inflation of 5.8 percent per year (see the
Inflation Adjustment discussion in section II.A.2.a of this document).
An addition of $11,721,000 to ensure that fees cover a
proportionate share of the increased costs that FDA will have to pay
for rent and rent-related costs and one-time costs of the required move
to the White Oak facility in Silver Spring, MD. These costs would be
added to the fee total to maintain the needed level of review staffing
(and associated direct costs) while also paying for these critical
nondiscretionary operating costs.
An addition of $20,000,000 to adjust the base amount of
fee revenues to cover significant increases in FDA's drug review
workload that occurred during PDUFA III, but were not captured by the
workload adjustment provision of PDUFA III and which we are
recommending be revised for PDUFA IV (see the Workload Adjustment
discussion in section II.A.2.b of this document). The PDUFA
[[Page 1747]]
III workload adjuster captured workload increases associated with
increased numbers of submissions, but did not capture workload
increases associated with the increased level of effort for each
submission. FDA documented that the review effort for each submission
increased significantly during PDUFA III. The investigational new drug
workload increased markedly because of significantly more meetings per
investigational new drug (IND) submitted and because of a sharp
increase in the number of special protocol assessments submitted for
FDA review.
An addition of $37,890,000 to fund the proposed
enhancements to the PDUFA program, including enhancements to the
premarket review program and proposals for modernizing and transforming
the postmarket safety system.
The sum of these components yields the proposed target revenue figure
of $392,783,000. ($392,883,000 = $305,455,400 + $17,716,600 +
$11,721,000 + $20,000,000 + $37,890,000).
2. Proposed Revisions to the Inflation Adjustment and Workload
Adjustment Applied to User Fees
(a) Inflation Adjustment: The fee revenue amounts for PDUFA III
were stated in FY 2003 dollars and the proposed fee revenue amounts for
PDUFA IV are stated in FY 2008 dollars. Before fees were assessed each
year in PDUFA III, the fee revenue target was increased and compounded
based on the higher of either: (1) The CPI/U over the latest 12-month
period or (2) the most recent increase in pay for Federal employees in
the Washington, D.C. area, compounded since FY 2003. The rate of pay
for employees in the Washington D.C. area was higher in all but one
year, and the PDUFA III inflation adjustment has resulted in average
annual inflation increases of 4.16 percent over each of the last 5
years. However, the actual cost of pay and benefits per full time
equivalent (FTE) is increasing faster than this factor. Data from the
past 5 years shows that the actual cost of salary and benefits has
increased at an average rate of 5.8 percent per year during the past 5
years for FDA. FDA proposes to recommend changing the provision for
calculation of the inflation adjustment to add to it a third factor--
FDA's actual rate of increase in the costs of pay and benefits per FTE
during the most recent 5-year period--and the annual adjustment would
be based on the highest of the three factors each year.
(b) Workload Adjustment: The workload adjuster currently applied in
PDUFA makes adjustments for changes in numbers of applications, but it
is flawed in two ways. First, the surrogate for IND workload in the
current workload adjuster is the number of new commercial INDs
submitted each year. Since each one of these INDs is active for several
years, the number of new applications submitted in any 1 year is a poor
surrogate for total IND workload. Second, the workload adjuster does
not take into account increases in work associated with active INDs,
NDAs, and BLAs. During PDUFA, there has been a substantial increase in
the numbers of meetings and special protocol assessments per IND
submission. However, the current workload adjuster only takes into
consideration changes in numbers of submissions--not additional
activity required per submission. Since FY 2002, the number of meetings
per commercial IND has increased by close to 30 percent, and the number
of special protocol assessments is up over 90 percent. This same
phenomenon occurs with NDAs as well, but to a somewhat lesser extent.
To remedy these flaws, the following changes are proposed: First,
we recommend changing the surrogate for IND workload in the statute
from the numbers of new commercial INDs received each year to the total
number of active commercial INDs each year. Active INDs are those that
have had at least one submission in the previous 12-month period.
Second, we recommend using an adjuster applied to the numbers of NDA/
BLAs and INDs. The proposed adjuster would adjust the numbers of these
applications in proportion to the impact on workload of increased
meetings and special protocol adjustments for INDs and for increased
meetings, labeling supplements, and annual reports for NDAs and BLAs.
Under the proposed change to the workload adjuster, we also propose
to contract with an independent accounting firm to examine the new
adjuster and make recommendations, if needed, for further improving
this adjuster.
3. Technical Changes to Increase Administrative Efficiency of the User
Fee Program
The FDA is proposing to recommend several technical changes to
PDUFA to simplify some of FDA's current procedures, to clarify the
original intent of several PDUFA definitions, and to remove potential
ambiguity. FDA's analysis of the impact of these changes indicates that
they would be revenue-neutral and would have a minimal impact on
industry fee-payers. These technical proposals include the following:
(a) Simplify the definition of ``human drug application'' to
include all new drug applications under section 505(b) of the Federal
Food, Drug, and Cosmetic Act;
(b) Amend the definition of ``small business'' for the purpose of
fee collection to reinstate language from the original PDUFA statute
that specifies that to qualify as a small business, the company may not
have an approved product already introduced in or delivered for
introduction into interstate commerce;
(c) Include capsules, tablets, and lyophilized products as examples
in the definition of final dosage form to provide clarification of what
constitutes a finished dosage form;
(d) Revise the waiver provisions to clarify that the person named
as the applicant and assessed the user fee is the person who is
eligible to request a waiver or reduction of fees;
(e) Change the date for the calculation of the adjustment factor so
it can be calculated before the President's budget goes to Congress;
(f) Clarify that for fee purposes, applications withdrawn before
filing will be treated as applications that FDA refuses to file, and
that they will be assessed a full fee if filed again or filed over
protest;
(g) For user fee purposes, reinstate the definition of ``person''
to include affiliates, as enacted under FDAMA
(h) Delay offsets for collections in excess of appropriations in
any year to the final year of the PDUFA program and make offsetting
reductions only if cumulative fees collected over the first 4 years
exceed cumulative appropriations for fees over the same period; and
(i) Revise the definition of ``prescription drug product'' for the
purpose of fee collection, to clarify the exclusion of products on
discontinued product lists maintained by Center for Drug Evaluation and
Research (CDER) and Center for Biologics Evaluation and Research
(CBER).
B. Enhancing the Process for Premarket Review
In the premarket review area, several changes were made in PDUFA
III as compared to PDUFA II. These are outlined as follows:
Continuous marketing application pilot programs: Two pilot
programs were established under PDUFA III to test whether providing
early review of selected applications and additional feedback and
advice to sponsors during drug development for selected products
[[Page 1748]]
can further shorten drug development and review times. Pilot 1 involved
a commitment on the part of FDA to review and provide feedback to the
sponsor within 6 months of submission of ``reviewable units'' of an
application in advance of the submission of the complete application.
This pilot program represented an extension of the ``rolling review''
program begun under FDAMA and was limited to applications that had
received a Fast Track designation. Pilot 2 involved a commitment on the
part of FDA to provide more structured and extensive interaction and
feedback to sponsors for up to one Fast Track application per review
division during drug development. This pilot represented an extension
of the usual interactions between FDA and sponsors during drug
development. To evaluate the costs and benefits of these pilots, FDA
commissioned an independent assessment. The CMA Pilot 1 Evaluation and
Pilot 2 Preliminary Evaluation Studies--Final Report is available on
the FDA Web site at https://www.fda.gov/ope/CMA/CMAFinalReport.pdf.
After review of the findings, FDA and industry representatives have
agreed that although the pilots demonstrated value in some areas, the
overall added benefits of the programs did not justify their costs to
FDA. Therefore, FDA is proposing to recommend that the CMA pilot
programs will not be continued in PDUFA IV.
First cycle review performance: In PDUFA III, FDA
committed to several new goals that were focused on improving the
effectiveness and efficiency of first cycle reviews in an attempt to
decrease the number of multi-cycle reviews without compromising FDA's
traditional high standards for approval. The first new goal was for FDA
to notify the applicant of any substantive deficiencies identified in
an application during the initial filing review. The identification of
such deficiencies was to be communicated to the applicant within 14
days of the 60-day application filing date, which is commonly known as
a ``74 day letter.'' FDA has consistently met or exceeded the goals for
communication of these early deficiencies. The second new goal was for
FDA to develop and publish a final joint CDER/CBER guidance on GRMPs.
FDA published a final GRMP final guidance on March 30, 2005, entitled,
``Guidance for Review Staff and Industry on Good Review Management
Principles and Practices for Prescription Drug User Fee Act Products;
Availability,'' at https://www.fda.gov/OHRMS/DOCKETS/98fr/05-6404.htm
(70 FR 16507; March 31, 2005). As part of the goals, FDA also committed
to develop and implement a training program for all CDER and CBER
review staff on the GRMPs. FDA met the goal for training all review
staff on the GRMPs and has incorporated training on the guidance as
part of new reviewer training. Finally, FDA committed to commission an
independent consultant evaluation of the factors associated with the
conduct of first cycle reviews. The first study was a retrospective
analysis of first cycle reviews for NME and original BLAs submitted in
FY2002-2004, and is available on the FDA Web site at https://
www.fda.gov/ope/pdufa/PDUFA1stCycle/pdufa1stcycle.pdf. The second study
was a prospective study of first cycle reviews for NME and original BLA
submissions starting in FY05 and continuing through FY07, and is
currently in progress. FDA is proposing to recommend the continuation
of first cycle review performance initiatives.
Independent consultants for biotechnology clinical trial
protocols: This initiative allowed applicants for certain biotechnology
products to request that FDA engage an independent expert consultant,
selected by FDA, to participate in the agency's review of the protocol
for clinical studies that were expected to serve as the primary basis
for a claim. FDA has received no requests under this initiative during
PDUFA III and, after discussions with industry representatives, FDA is
proposing not to include this initiative in the recommended PDUFA IV
program.
1. Proposed Recommendations for Enhancement of Premarket Review Process
In the area of premarket review, FDA is proposing to recommend
enhancements in two areas: (1) Good review management principles and
(2) expediting drug development.
(a) Expanding Implementation of GRMPs: In the area of GRMPs, we are
proposing to recommend further enhancements associated with notifying
applicants at the time of the ``74-day letter'' of the anticipated
timeline for review of the application, including the anticipated date
for initiation of discussions regarding product labeling and any FDA
requests for postmarketing study commitments (PMCs).
Historically, labeling discussions have been initiated at the late
stages of a review, often in the last week before approval. Similarly,
the agency often communicates requests for postmarketing commitments
late in the review cycle. Initiation of discussion of these important
elements of the review of an application late in the review cycle is
often due to the inability of FDA to complete its review of the
application earlier because of an imbalance between workload and
available review staff time. Late initiation of these important
discussions is not consistent with the best practices that FDA has
identified and published in the GRMP guidance.
An understanding on the part of both the reviewers and the
applicant of the process and timeline for the review would facilitate
an efficient and scientifically sound review. FDA believes that
adhering to a timeline that includes earlier initiation of discussion
of labeling, coupled with the new physician labeling regulations (see
Requirements on Content and Format of Labeling for Human Prescription
Drug and Biological Products at https://www.fda.gov/OHRMS/DOCKETS/98fr/
06-545.pdf) (71 FR 3922, January 24, 2006), would result in clearer,
more readily understandable labeling for new products. Furthermore, FDA
believes that initiation of discussions of possible postmarketing
commitments earlier in the process would allow for the commitments to
be more focused on the data needed to further inform the best use of
the products. We also expect that earlier discussion of PMCs would help
to ensure that the agreed to studies and study schedules are feasible,
thereby improving the timely completion of the studies by the
applicant.
The proposed recommendations under the enhancements for GRMP are
also intended to encourage applicants to provide FDA with applications
that are complete for review at the time of submission. The submission
of complete applications would allow FDA to effectively manage and
adhere to its review schedule and, ultimately, may result in faster
access to these new products without any compromise to FDA's
traditional high standards for approval. Consequently, FDA believes
these proposed recommendations to be in the best interest of the
agency, the applicant, and, ultimately, the public health.
(b) Expediting drug development: One of the things that the agency
can do to enhance the development of new and beneficial drugs is to
provide guidance to industry to clarify current agency thinking on a
variety of topics including, among other things, clinical trial design.
Our experience and insight, gained through years of review, can help
the industry avoid wasting scarce research and development resources on
clinical trials that are not likely to produce results because of
flawed designs. By clarifying the agency's
[[Page 1749]]
expectations regarding the nature of data needed to support certain
types of claims, we can allow the industry to focus their efforts on
useful trials and decrease less useful experimentation. This would have
the benefit of decreasing exposure of subjects to unapproved products,
decreasing the amount of time required to bring a beneficial new drug
to market, and, possibly, decreasing the total cost of bringing the new
drug to market, which should translate to lower drug prices for the
consumer.
Guidance development by the agency requires substantial time
commitments from those who are already heavily involved in the review
effort. The PDUFA IV proposal includes increased user fees that would
be used to fund additional staff resources to develop the following
guidances to enhance clinical drug development (the FY dates for each
guidance represent FDA's proposed commitment to publish a draft
guidance on that topic by no later than the end of FY listed):
1. Clinical Hepatotoxicity--FY 2008. This guidance would address
how to evaluate a drug for possible hepatotoxicity during drug
development and how FDA will review an application to look for signs
that a drug may be a significant hepatotoxin.
2. Non-inferiority Trials--FY 2008. This guidance would describe
FDA's perspective on the design of noninferiority trials. Topics
addressed are expected to include how to select the active control, how
to document the effect size of the active control versus placebo, and
how to establish the noninferiority margin of interest.
3. Adaptive Trial Designs--FY 2008. This guidance would explain
FDA's perspective on the use of adaptive trial designs during drug
development. Topics to be addressed include the definition of adaptive
trial designs, recommended designs, and how the statistical issues
should be addressed in analyzing trials.
4. End of Phase 2(a) Meetings--FY 2008. This guidance would outline
the procedures and data needed for an end-of-phase 2a (EOP2a) meeting.
The EOP2a meetings are intended to facilitate FDA interactions with a
sponsor earlier in the design of the development program to maximize
the value of the phase 2 program with the overall goal of making drug
development more efficient and effective.
5. Multiple Endpoints in Clinical Trials--FY 2009. This guidance
would describe FDA's perspective on the appropriate procedures and
analyses for trials with multiple endpoints (e.g., a trial with
multiple co-primary endpoints).
6. Enriched Trial Designs--FY 2010. This guidance would focus on
approaches to enrich the clinical trial population to better define the
efficacy or safety of the drug under development.
7. Imaging Standards for Use as an End Point in Clinical Trials--
FY 2011. This guidance would focus on the use of images as important
endpoints in controlled clinical trials. Issues would include image
acquisition, archiving, and blinded reading.
The commitment, under this part of the proposed PDUFA IV program,
would allow us to pursue the development and publication of several
guidance documents to facilitate the development of new, life-saving
therapies, moving them more efficiently from the laboratory to the
bedside.
In addition to funding the development of guidances, under PDUFA IV
we are proposing to collect user fees to hire additional staff to free
up reviewer time to enable greater participation in scientific research
collaborations that will ultimately help clarify regulatory pathways
for new technologies and potential new biomarkers for drug safety and
effectiveness. For example, FDA intends to participate in workshops
with representatives from the scientific community (including industry,
academia, and other interested stakeholders) to further the science
toward development of guidance documents in the following areas:
1. Predictive toxicology--Emerging science such as toxicogenomics,
proteomics, metabolomics, and molecular imaging, is expected to yield
more sensitive, specific, and informative tests for drug organ toxicity
than the toxicology screening techniques currently in use. FDA
reviewers will need to participate extensively in the design of studies
intended to qualify these new safety tests for regulatory uses.
2. Biomarker Qualification--Biomarkers are frequently used during
drug development to understand the effect of a drug on biologic systems
and to predict clinical response. Before biomarkers can be used for
regulatory decision making they must be qualified. FDA expertise will
be needed on an ongoing basis in the effort to select and test
candidate biomarkers for qualification. FDA reviewers will need to
participate in the design of the definitive studies intended to qualify
the biomarker for a specific regulatory use.
3. Missing Data--In controlled clinical trials it is often
impossible to ensure that every data element described in the protocol
is collected for every study subject. For example, subjects often
discontinue participation in a trial early and do not return for
further study visits. The question of how to handle missing data when
analyzing the results of a trial is a very complex one, and FDA would
expect to work in collaboration with outside stakeholders to further
explore the science of this issue and develop appropriate procedures.
Finally, under the proposal for PDUFA IV, user fees would be used
to support FDA participation in workshops and other public meetings to
explore new approaches to a structured model for benefit/risk
assessment. The results of these interactions would be used to assess
whether pilot(s) of such new approaches can be conducted during PDUFA
IV. These efforts may lead to the development of guidance documents.
Under PDUFA IV, FDA proposes to collect an additional $4,600,000 in FY
2008 and, in subsequent years, adjusted for inflation and workload, to
support at least 20 FTEs to engage in the collaborations with outside
stakeholders described previously.
2. Improving the IT Infrastructure for Human Drug Review
Under PDUFA III, we agreed to certain performance goals associated
with better management of information technology (IT) resources and
improved consistency of IT practices across the human drug review
program. Under PDUFA III, we centralized accountability for PDUFA IT
funding under the Chief Information Officer (CIO); established an IT
Project Management Office to develop and implement processes policies,
based on the Capability Maturity Model Integration process improvement
approach to improve software development practices; implemented the
electronic Common Technical Document standard for electronic regulatory
submissions; established a common secure single point of entry for the
receipt and processing of all electronic submissions, commonly called
the FDA Electronic Submissions Gateway; and established a common
approach to managing desktop hardware and software configurations. We
are now in the process of establishing a common approach for secure e-
mail that will be implemented throughout the PDUFA program. Following
provisions in the PDUFA III commitment letter, we have also met
quarterly with industry representatives to discuss progress
[[Page 1750]]
towards these IT goals and to address technical implementation issues.
These accomplishments have built a strong foundation for further
progress toward an IT environment that better serves the human drug
review program.
Under PDUFA IV, we recommend collection of an additional $4,000,000
annually, starting in FY 2008 to enable the agency to commit to several
IT performance goals that would move FDA and industry towards an all-
electronic environment, which would increase the efficiency of the
review process. Under these proposed goals, we would commit to develop
a 5-year IT plan that would lay out the technical approach for
achieving a more integrated, standards-based electronic regulatory
submission and review environment. The plan would help FDA, industry,
and stakeholders make related IT investments in a more coordinated
manner. By the end of PDUFA IV, following implementation of these
proposed goals, human drug application sponsors would be able to send
in their electronic applications with automated cross-links to
previously submitted data and information, so that they only have to
submit things once. In addition, FDA reviewers would be able to
retrieve all relevant submissions and related data electronically from
their work stations and would have efficient tools for searching and
analyzing data to support their reviews. These capabilities would
enable more efficient and reliable management of regulatory
submissions.
By the end of PDUFA IV, if resources are provided as expected, we
intend to have the capability to handle two-way transmission of
regulatory correspondence with industry, which would accelerate the
movement toward an all-electronic submission and review environment.
To determine whether we are moving towards achieving the IT goals
described in PDUFA IV, we further propose to track several key
performance indicators of the adoption rate of electronic submissions
and the technical error rates associated with those submissions, so
that we can more closely monitor progress toward the all-electronic
environment.
Finally, in the recommended IT performance goals for PDUFA IV, we
propose a cost-effective approach that minimizes expenditures on
existing legacy systems and redirects those funds toward the
development of new common systems that are better coordinated and more
flexible.
C. Modernizing and Transforming the Postmarket Drug Safety System
In PDUFA III, for the first time, FDA was authorized to spend user
fees revenues to fund improvements in drug safety. This change provided
important new resources to help improve postmarket safety but our
experience has shown that further improvements can be achieved. The
definition of the ``process for the review of human drug applications''
in section 735 of PDUFA describes which products PDUFA funds can be
used for in terms of postmarket safety review as well as the length of
time after product approval PDUFA funds can be used for such safety
review. Specifically, 735(6)(F) states: ``In the case of drugs approved
after October 1, 2002, under human drug applications or supplements:
collecting, developing, and reviewing safety information on the drugs,
including adverse event reports, during a period of time after approval
of such applications or supplements, not to exceed three years.''
In addition, the PDUFA III Reauthorization Performance Goals and
Procedures document stated that user fees may be used ``for a period of
up to two years post-approval for most products and for a period of up
to three years for products that require risk management beyond
standard labeling * * *.'' The stated purpose of this language was to
provide user fees to review an applicant's implementation of risk
management plans for this period of time and to allow for evaluation of
study reports, product use, and other safety activities. Drug safety
activities outside of the specified timeframe were to be funded with
appropriated dollars.
As part of the PDUFA IV program, we propose to recommend further
enhancing the program by removing the language that limits the spending
of user fees outside of the specified timeframe. Current data show that
safety issues can arise after a drug has been on the market for 8 or
more years. A recent FDA analysis of safety-related label changes made
between October 2002 and August 2005, for all drug products with a
labeling change, found that the total number of safety-related label
changes exceeded 160 changes for drugs 3 years postapproval and
remained at or above that high level until 8 years postapproval before
starting to decline. All stakeholders agree that the current
limitations on use of funds for postmarketing safety-related activities
present an opportunity for improving the agency's ability to optimally
support adverse event surveillance, detection, evaluation, and
management. Enhancing the program by eliminating such limitations would
help both FDA and drug sponsors because safety assessments of drug
products by both FDA and sponsors are necessary for drugs over time to
adequately manage risks, regardless of approval date. Increased
resources, including from PDUFA funds, would enable FDA to engage in
safety review activities, such as studies of drugs in the same class
approved before and after October 1, 2002, to adequately assess
significant drug safety issues. The current description of
postmarketing safety activities in the definition of the ``process for
the review of human drug applications'' could also be revised to better
reflect the broad variety of activities that are important to
postmarket safety review.
As part of the reauthorization of PDUFA, FDA proposes changing the
statute to eliminate the statutory restrictions so that PDUFA fees
could be used to assess safety issues postapproval, independent of a
product's approval date and would allow the agency to review the drug's
safety in whatever time frame risks arise using all available
resources. This change would provide much needed support for timely,
predictable, consistent, and scientifically sound regulatory
decisionmaking and would work towards a fully integrated evaluation of
drugs and biologics throughout their life cycle.
In addition, we propose expanding the description of postmarket
safety activities to capture a broader range of activities related to
postmarket safety review. For example, FDA would use $29,290,000 in new
user fee funds to enhance and modernize the current U.S. drug safety
system. We would adopt new scientific approaches, improve the utility
of existing tools for the detection, evaluation, prevention, and
mitigation of adverse events associated with drugs and biological
products. In addition, FDA would use these funds to continue to enhance
and improve communication and coordination between pre- and postmarket
review staff. Potential activities in this area might include
integration of certain proposed recommendations made by the Institute
of Medicine (IOM) in their September 2006 report entitled, ``The Future
of Drug Safety: Promoting and Protecting the Health of the Public.''
PDUFA IV funds would also be used to support a number of activities
designed to modernize the process of pharmacovigilance. One key
initiative would be the implementation of an FDA contract to one or
more outside research organization(s) to conduct research on
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determining the best way to maximize the public health benefits
associated with collecting and reporting serious and nonserious adverse
events occurring throughout a product's life cycle. Studies under this
contract would answer such central questions as the number and types of
safety concerns that are discovered by various types of adverse event
collection, the age of the medical products at the time such safety
concerns are detected, and the types of actions that are subsequently
taken and their ultimate effect on patient safety.
PDUFA IV funds would also support the development of a guidance
document to delineate epidemiology best practices. Epidemiologic
studies using large automated databases are increasingly being
performed to evaluate drug safety. These studies and safety analyses
are complex and employ a variety of nonstandardized analytic methods
and assumptions. During the course of PDUFA IV, FDA, with input from
academia, industry, and others from the general public, would hold a
public workshop to identify best practices in this emerging field,
ultimately developing a document that addresses epidemiology best
practices and provides guidance on how to carry out scientifically
sound observational studies using quality data resources.
Another critical part of the transformation of the drug safety
program would be maximizing the usefulness of tools used for adverse
event detection and risk assessment. To achieve this end, data other
than spontaneous adverse event reports, including population-based
epidemiological data and other types of observational data resources,
would be used and evaluated. Access to these types of data would expand
our capability to carry out targeted postmarketing surveillance, look
at class effects of drugs, and potentially carry out signal detection
using data resources other than reports from FDA's adverse event
reporting system (AERS). PDUFA IV funds would be used to obtain access
to additional databases and increase program staffing with
epidemiologists, safety evaluators, and programmers who can use these
new resources.
As mentioned previously, the PDUFA III Reauthorization Performance
Goals and Procedures document provided user fees to review
implementation of a risk management plans for a limited period of time
and to allow for evaluation of study reports, product use, and other
safety activities. Risk communication and management have now become a
routine part of human drug review, yet many of the risk management and
risk communication tools the industry uses remain unproven and
unstandardized. To promote more effective and consistent use of these
tools to mitigate the risk of drugs and biological products, under
PDUFA IV, with input from academia, industry, and others from the
general public, we would conduct an annual systematic public discussion
and review of the effectiveness of one to two risk management programs
and one major risk management tool per year. Reports from these
discussions would be posted on the FDA Web site.
FDA would also use PDUFA IV fees to enhance the agency's AERS and
surveillance tools, to strengthen its IT infrastructure to support
access and analyses of externally linked databases, and to support a
safety workflow tracking system. This support for drug and biological
product safety-related IT systems is critical to ensure the best
collection, evaluation, and management of the vast quantity of safety
data received by FDA.
FDA would use PDUFA IV funds to develop and periodically update a
5-year plan describing the range of activities designed to enhance and
modernize the drug safety system. FDA would publish and seek public
comment on an initial plan for these activities and conduct an annual
assessment of progress against the plan to be published on FDA Web
site. In addition to progress against the specific modernization
activities described previously, the annual report would include an
update on FDA efforts to facilitate the interactions between the Office
of New Drugs and the Office of Surveillance and Epidemiology related to
the process of evaluating and responding to postmarketing drugs safety/
adverse event reports. FDA would publish updates to the modernization
plan as FDA deems necessary and post on FDA's Web site draft revisions
to the plan, soliciting comments from the public on those draft
revisions and then carefully considering all public comments before
completing and publishing updates to the plan.
Another recent study by the IOM, entitled ``Preventing Medication
Errors: Quality Chasm Series,'' (July 20, 2006), estimates that, on
average, every hospitalized patient is subject to at least one
medication error per day. These errors lead to costly morbidity and
mortality. The IOM concluded that drug names that look or sound
similar, in addition to the layout and presentation of important drug
information on the label, labeling, and packaging of drug products
increase the risk of medication errors. The IOM report recommended that
the FDA, the pharmaceutical industry, and other stakeholders should
collaborate in several areas to improve methods for naming and labeling
drug products and communicating medication information to providers and
consumers and advised the FDA to develop guidance documents for
industry related to drug naming, labeling, and packaging.
Using PDUFA IV funds, FDA would implement various measures to
reduce medication errors related to look-alike and sound-alike
proprietary names as well as factors such as unclear label
abbreviations, acronyms, dose designations, and error-prone label and
packaging designs. Activities to be funded include guidance
development, review performance goals, and initiation of a pilot
program to explore a different paradigm for proprietary name review.
Fees would provide the resources FDA needs to publish three
guidances to industry: (1) Guidance on the contents of a complete
submission package for a proposed proprietary drug/biological product
name; (2) guidance on best practices for naming, labeling, and
packaging drugs and biologics to reduce medication errors; and (3)
guidance on proprietary name evaluation best practices. These
guidances, developed after consultation with industry, academia, and
others from the general public, would provide a scientifically sound
and consistent approach to the selection, evaluation, and review of
proprietary names and would also create a framework for best practices
for the layout and design of drug labels and packaging to prevent or
minimize medication errors.
In addition, under the proposed PDUFA IV program, FDA would commit
to a performance goal of 180 days for reviewing proprietary names
submitted during the IND and NDA phases. For submissions received as
part of an IND, submitted as early as the end of phase 2 of drug
development, FDA would increase the percentage of submissions subject
to this goal, from 50 percent in year 1 to 90 percent in year 4 of the
program. In a similar phased-in fashion, for submissions received as
part of an NDA or BLA, FDA would review 50 percent (in year 1)
increasing to 90 percent (in year 4) of proprietary name submissions
within 90 days of receipt. Commitment to review goals would enhance the
timeliness and predictability of proprietary name review.
During PDUFA IV, FDA proposes to develop and implement a pilot
program that shifts the responsibility for testing proposed proprietary
names from FDA to the pharmaceutical industry. This
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program would enable pharmaceutical firms participating in the pilot to
evaluate proposed proprietary names and submit the data generated from
those evaluations to FDA for review prior to approval. Using this more
traditional FDA review role was recommended by the IOM in November 1999
report, entitled ``To Err Is Human: Building a Safer Health System, ''
as well as the HHS Advisory Committee on Regulatory Reform in November
of 2002 Secretary's Advisory Committee on Regulatory Reform, November
21, 2002, https://regreform.hhs.gov/meetinginfo/november_
meetinginfo.htm. The proposed pilot would allow this approach to be
evaluated for its contribution to the efficiency and timeliness of
proprietary name review.
III. What We Are Proposing to Recommend for Review of Direct-To-
Consumer Advertising
In addition to our proposed recommendations for enhancements to the
current human drug review program, we are proposing to recommend a
program separate from, but related to, PFUFA assessing fees for
advisory reviews of DTC television advertisements. Research has shown
there can be benefits associated with DTC prescription drug television
advertising, such as informing patients about the availability of new
treatment options and encouraging patients to see a physician about an
illness for the first time. Notwithstanding these benefits, concerns
have arisen about the effects of DTC television advertisements on
prescribing practices and prescription drug use. Companies have the
option of submitting their proposed advertisements to FDA for advisory
review before publicly disseminating them, which gives them with the
benefit of FDA input on whether or not the adv